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When I returned to San Francisco I projected a pleasure journey to Japan and thence westward around the world; but a desire to see home again changed my mind, and I took a berth in the steamship, bade good-bye to the friendliest land and livest, heartiest community on our continent, and came by the way of the Isthmus to New York—a trip that was not much of a pic-nic excursion, for the cholera broke out among us on the passage and we buried two or three bodies at sea every day. I found home a dreary place after my long absence; for half the children I had known were now wearing whiskers or waterfalls, and few of the grown people I had been acquainted with remained at their hearthstones prosperous and happy—some of them had wandered to other scenes, some were in jail, and the rest had been hanged. These changes touched me deeply, and I went away and joined the famous Quaker City European Excursion and carried my tears to foreign lands.
Thus, after seven years of vicissitudes, ended a “pleasure trip” to the silver mines of Nevada which had originally been intended to occupy only three months. However, I usually miss my calculations further than that.
If the reader thinks he is done, now, and that this book has no moral to it, he is in error. The moral of it is this: If you are of any account, stay at home and make your way by faithful diligence; but if you are “no account,” go away from home, and then you will have to work, whether you want to or not. Thus you become a blessing to your friends by ceasing to be a nuisance to them—if the people you go among suffer by the operation.
(Roughing It)

From Editorial narrative following 15 Dec 1866:
It was a memorable trip. The first night out from San Francisco a violent storm nearly swamped the America, terrifying the passengers in steerage and making virtually everyone seasick. “Happily I escaped,” Clemens observed, “had something worse.” This unnamed illness kept him confined, though not completely solitary, both before and during the voyage. On 28 December he reached San Juan del Sur and, after a two-day trek overland, arrived at Greytown, where he boarded the San Francisco, bound for New York. On 2 January, one day out of Greytown, cholera struck. By 5 January three were dead and a fourth mortally ill. Thinking of the most recent victims—“both so well when I saw them yesterday evening” Clemens wrote in his notebook, “I almost realize that I myself may be dead to-morrow” (N&J1, 245, 277).

Seven nerve-racking days later, on 12 January, the San Francisco steamed into New York harbor; by then seven had died (four from cholera), and there had probably been more deaths among the twenty-one passengers who fled the ship at Key West. Mark Twain described his arrival for the Alta:

We swore the ship through at quarantine, which was right—she hadn’t had any real cholera on board since we left Greytown—and at 8 o’clock this morning we stood in the biting air of the upper deck and sailed by the snow-covered, wintry looking residences on Staten Island—recognized Castle Garden [in the Battery]—beheld the vast city spread out beyond, encircled with its palisade of masts, and adorned with its hundred steeples—saw the steam-tug and ferryboats swarming through the floating ice, instinct with a frenzied energy, as we passed the [East] river—and in a little while we were ashore and safe housed at the Metropolitan. (SLC 1867 [MT00522])

Mark Twain Project

From page 369-70:   The Life of Mark Twain: The Early Years, 1835-1871

The FAIR WEATHER was short-lived. The first evening the ship encountered a “great tempest—the greatest seen on this coast for many years,” Sam Clemens noted. ‘The night was pitch-black and the third-class passengers in steerage were imprisoned after “the hatches were battened down and canvassed over.’ Fortunately, Sam occupied a berth on the upper deck, so the sea ‘did not seem so rough to us as it did to those below.” The problem, he explained, was that the ship was too heavy at “the head & just doggedly fought the seas, instead of climbing over them. Nearly everybody seasick.” Sam escaped mal de mer because he “had something worse’—perhaps the cold he claimed to have contracted on the Divide between Gold Hill and Virginia City, Nevada, or perhaps a recurrence of venereal disease. In any event, the crew moved cargo aft and the lifeboats “on the after-guard were pumped full of water. These precautions eased the ship’s head and saved her.” A wave that broke over the ship about midnight carried away twenty feet of the bulwarks forward, & the forward cabin was drenched with water & the steerage fairly flooded. A case of claret floated, in a state room in the forward cabin—then the water must have been 6 inches deep—if a case of claret would float or wash at all. A man’s boots were washed to far end of room, Various things were afloat. Must have been flooded in steerage. They prepared the boats for emergencies.

The gale was so severe, Sam reported to his San Francisco Alta California readers, that “miners from Washoe and California and ‘web-feet’ from Oregon, who had never prayed in their lives before, perhaps, knelt down and did the best they could at it on short notice.” It “proved the America to be a staunch and reliable vessel” and the captain “a thoroughly competent officer.’ The ship was commanded by Edgar “Ned” Wakeman, who had delivered the “scoofy oysters” to San Francisco aboard the John L. Stephens in December 1864.

Sam credited Wakeman with saving the ship from a hurricane and soon befriended him, ‘Td rather travel with that old portly, hearty, jolly, boisterous, good-natured old sailor” than “with any other man I ever came across,” he wrote in his journal a week after they left San Francisco. ...

See SLC to Minnie Wakeman-Curtis, 5 Oct 1877, Hartford, Conn. (UCCL 01493).

The voyage was marred by the death on Christmas Eve of an infant girl after an illness of only two days. All of the passengers acted as though “they were related by blood” to her, Sam wrote the Alta California, because travelers ‘on a long voyage become as one family.” At 10:00 a.m. on Christmas Day she was buried at sea after a brief sermon by the Reverend S. M. Fackler, an Episcopal minister from Boise, Idaho.’

There is a possibility that the "something worse" Sam suffered on the voyage was actually a case of cholera.   Matthew Seybold, September 9, 2021, in a message archived in Twain-L, speculated on this possibility:

The Surgeon General officially declared a cholera epidemic in San Francisco the same month the *America *departed from the city's port. Then, as now, it is probably reasonable to suspect the outbreak was extensive well before it was officially registered, and San Francisco was one of the last U.S. metropoles to declare the outbreak which spread from coast to coast in 1866, which turned out to be the peak year for cholera in the U.S. during the prolonged midcentury pandemic (which began, if I'm remembering correctly, in Russia).
So, I don't think it is at all unlikely that cholera was introduced from the outset, although it definitely worsened as the voyage progressed, and both ships - the *San Francisco *and the *America - *returned to their origins (NYC & SF) with numerous casualties. There are conflicting totals, through the ships and passengers, who transferred between vessels at Nicaragua. Cholera is, of course, bacterial, and it would've been incredibly difficult to remove it from ships, even after infected. Predictably (and xenophobically), newspaper reports treated cholera as an exotic South American disease even after there were ongoing outbreaks across US, including in NYC and SF. These accounts frequently blame, specifically, a group of soldiers from which many casualties came for the sorry conditions aboard the *America *and *San Francisco*. (up to and including death) before the *America *reached Nicaragua (or took aboard said soldiers).

Page 371-3    The Life of Mark Twain: The Early Years, 1835-1871

The America landed at San Juan del Sur, on the west coast of Nicaragua, on December 28, and the passengers began their three-day trek across the isthmus the next day. They traveled by Stage to Virgin Bay on the shore of Lake Nicaragua, where at 2:00 a.m. they boarded steamers that carried them to San Juan del Norte, or Greytown, by daylight. Charley Webb, who had passed through Greytown in 1862 en route to California, described it as “an insignificant little place” with houses “built chiefly of bamboos and bananas and thatched with palm leaves.” Sam was impressed by its “native thatched houses” where “coffee, eggs, bread, cigars & fruit” were for sale: “delicious—10 cents buy pretty much anything & in great quantity. Californians cant understand how 10 or 25 cents can buy a sumptuous lunch.” As usual, too, he adored the local women as if they were forbidden fruit: “They are virtuous according to their lights, but I guess their lights are a little dim. .. . Two of these picturesque native girls were exceedingly beautiful— such liquid, languishing eyes! such pouting lips! such glossy, luxuriant hair! such ravishing, incendiary expression! such grace! such voluptuous forms, and such precious little drapery about them!”

Amid a downpour on January 1, 1867, Sam and the other passengers finally embarked for New York on the steamer San Francisco." The ship had suffered repeated mechanical problems en route to Nicaragua and, unbeknownst to Sam and his peers, was infected with cholera. Rather than quarantine the arriving passengers from the San Francisco for thirty days and await medical clearance to put the ship back into service, the company officials marched the passengers from the America to a death ship for their ten-day voyage to New York.

The first three cases of cholera in steerage were reported on January 2. The first of these patients died and was buried at sea by the end of the day, Reverend Fackler again officiating. A second victim died the next day and the corpse immediately cast overboard lest the disease spread. By January 5 three people had died and a fourth passenger was fatally ill; he soon died and “was shoved overboard half an hour afterward sowed up in a blanket with 60 pounds of iron.” The “cursed fools” in steerage were reticent to report their illness, fearing they would be charged all the money they possessed for medical help, so they let the diarrhea run two or three days & then, getting scared they run to the surgeon & hope to be cured, And they lie like blazes—swear they have just been taken when the doctor of course knows better. He asked a patient the other day if he had any money to get some brandy with—said no—the ship had to furnish it—when the man died they found a $20 piece in his pocket.

The captain began to inspect the ship every day for cleanliness and had the purser post a sign that no one aboard would be charged for medical care. Still, by the morning of January 5 the disease had infiltrated the second- and first-class cabins and, Sam noted, the passengers began to worry that the ship would be quarantined for thirty days in Key West. The consternation among the passengers and crew, including the doctor, was so great that some of them planned to abandon the ship at Key West “if quarantine regulations permit” and travel north by rail instead, Later in the morning Fackler fell ill; another passenger died and was buried at sea without benefit of clergy; by afternoon the minister had “bidden us all good-bye,” and he died before the end of the day, “Verily the ship is fast become a floating hospital,” Sam jotted in his journal, and “not an hour passes but brings its fresh sensation, its new disaster—its melancholy tidings.” He realized, given the gravity of the situation, “that I myself may be dead tomorrow.” “All levity” ceased and “a settled gloom is upon the face of the passengers,” who began to pray for the cool weather that would strike around Cape Hatteras, which would “drive away the sickness.” ‘The ship’s surgeon tried to “allay their fear by telling them he has all the medicines he wants,” when in fact he confided to Sam that he “had no medicines to work with—that he shipped the first time this trip & found the locker empty & no time to make a requisition for more medicines.” He tried to calm anxieties by assuring the passengers that the disease was “only a virulent sort of diarrhea” when it was “cholera & of the most virulent type.” In addition, the ship's engine broke down three times in midocean. “These things distress the passengers beyond measure,” Sam observed. “They are scared about the epidemic & so impatient to get along—& now they have lost confidence in the ship & fear she may break again in the rough weather that is to come.’ They worried, too, that the authorities at Key West would not permit “our pestilence-stricken ship” to “land there—but the Capt. says we are in sore distress, in desperate straits, & we must land, we will land, in spite of orders, cannon or anything else—we cannot go on in this way. If we do land, some of our people are going to leave—the doctor among them.” The ship was allowed to dock in Key West to refuel, though unknown to the port authorities the crew desperately needed to replenish its supply of medicines—and Sam wanted to exploit the opportunity to buy cheap cigars and brandy. He purchased “700 superb cigars at $4 a hundred— greenbacks—better cigars than I could get in Callifornia] for $25 a hundred in gold” and brandy for fifteen dollars a gallon. On the other hand, the local merchants extorted an exorbitant price for coal—two dollars per ton for a hundred tons, eight times the price in New York. After he learned about the sale, Sam did not expect “to find any Key West folks in Heaven.” “We remained at Key West a day and night,” he reported, and the ship raised anchor on the morning of the January 7 “with a thinned complement of people; for twenty-one passengers had quitted the ship on account of the cholera.” But some of the departees gave their “dinner & berth tickets to remaining friends in the steerage! ... I am glad they are gone, d——n them.” Fortunately, their generosity did not spread the contagion. Of the eighteen passengers “who were sick when we landed” at Key West, “eleven were already well again” by the time the ship departed “and all the fright about the disease was gone, Sam noted. “The dismal spell was removed,” ...

The shipping company planted a story in the New York Herald that blamed the passenger deaths not on an outbreak of cholera but on the consumption of unripe tropical fruit by the passengers during the crossing of Nicaragua, “an indiscretion against which the officers of the steamships” always cautioned people. That is, the company refused to assume responsibility for the fatalities. Sam apparently failed to challenge the malfeasance and corporate cover-up, though he must have known it was a lie, It was exactly the type of hypocrisy he relished exposing in later years. But on this occasion, as in Esmeralda and Humboldt Counties in Nevada in 1861, he was simply a prospector looking to strike it rich.