Cholera again struck New York City the year after the Civil War ended, and three years after the city had been wracked by the Draft Riots. Demographic changes in the city between 1849 and 1866 matched those in the period between 1832 and 1849: the city grew denser and the immigrant population expanded. By 1860, one in four New Yorkers — over 200,000 — had been born in Ireland. Irish immigrants had been the primary source of laborers on the Croton Aqueduct in the 1840s, and also laid the city's first sewer pipes in the 1850s (although the pipes were not located in Irish neighborhoods). Despite these contributions, the Irish were seen as a significant problem. Public opinion focused on the fact that Irish laborers were the primary aggressors in the Draft Riots, populated the city's worst slums, and seemingly pledged loyalty to the Italian Pope instead of the U.S. President. Compared to German and Scandinavian immigrants, who also flocked to the United States in mid-century and had fared better economically, the Irish were viewed as an unassimilable blight on the city.

New York, despite the Draft Riots and the interruption of trade with the South, prospered during the war years. Massive government spending in support of the war effort and high interest rates from banks had stimulated stock values. This income padded the pockets of New York's traditional elite while also creating the possibility for profit among an emerging class of stock traders and speculators. The growing wealth, visible in opulence along Fifth and Park Avenues, cast in sharp relief the expanding poverty of the downtown districts.

Nonetheless — or perhaps because of the disparity between wealth and poverty — city leaders, clergymen, and reformers believed that, beyond the good deed of helping the poor, it was in the elite’s own best interest to try to repair some of the city's deepest problems. Diseases that regularly sprang up in poor neighborhoods — such as typhus, dysentery, and typhoid — usually did the most severe damage in the slums. But sometimes they moved beyond the poor districts of the city to infect more "respectable" areas.

This was true of cholera, which had done more extensive damage to the city in 1849 than it had in 1832. New Yorkers were well aware that, given the density of the city's population, cholera's arrival in 1866 could be even more devastating. Armed with John Snow's research on how cholera traveled, the city was much better prepared to meet the threat posed by the disease as it again appeared in Western Europe in 1865.