As in 1832, the center of the outbreak seventeen years later was the Five Points slum district. And, as in 1832, those who could afford to leave the city for the summer did. The economic life of the city once again ground to a halt; even several of the city's churches closed their doors for the summer. For the most part, the city and the nation reacted to cholera's incursion in 1849 in the same ways as they had in 1832 — conventional wisdom said it was a scourge of the poor, who had weakened themselves with drink and vice and filth.

At the same time, many pious Americans who had witnessed more than a decade of capitalist expansion and materialist gain and consequently believed that greed had defeated spirituality in the nation’s values, interpreted cholera's presence as God's divine judgment. Many clergymen saw greed everywhere — in America's bloody war with Mexico, in the continued existence of slavery, in Sabbath-breaking, and in infidelity. Even President Zachary Taylor responded to the 1849 cholera outbreak by concluding that the nation needed to repent.

The reactions to cholera in 1832 and 1849, in common with responses to most disasters, tended to provide outlets for those promoting certain political or cultural agendas. Clergy, politicians, and elite reformers pointed to the devastation wrought by the disease as proof of how right they were, and how the disease reflected God's support for their respective causes. Disasters often provide the opportunity for national self-examination. In 1849, the meanings that were attached to cholera closely resembled the growing rifts within the nation around the questions of slavery, the direction of the emerging capitalist economy, and the responsibility of the state and elites towards the less fortunate.