Over the three centuries of New Orleans’s history, many have understood its recurring public-health disasters most notably from cholera, yellow fever, and HIV in a naïve, moralistic way as a sign of its intrinsically wicked population and as divine retribution for the city’s immoral culture. If we consider this history through Susan Sontag’s books, Illness as Metaphor and AIDS and Its Metaphors, and through sophisticated literary and cinematic representations of the plague-ridden city, we can see that this explanation of the city’s health challenges is driven by the attempt to create meaning from disease to grapple with the mysterious, fear-inducing nature of death. Sontag concludes that metaphors which attribute disease to the moral failings of the afflicted are destructive, stigmatizing those who suffer from disease. The truth about illness is that it has no greater meaning at all. The real source of New Orleans’s public health challenges is the overwhelming presence of water, an accident of geography. After giving an overview of New Orleans history with disease and Sontag’s insights on metaphor, the thesis analyzes seven novels and two films that take place in New Orleans and incorporate disease, assessing how equating disease with meaning impacts the reputation of New Orleans. These novels includes Alice Dunbar-Nelson’s The Goodness of St. Roch, Kate Chopin’s The Awakening, Ishmael Reed’s Mumbo Jumbo, Anne Rice’s Interview with the Vampire, Josh Russell’s Yellow Jack, and Valerie Martin’s A Recent Martyr and Property. The thesis analyzes Elia Kazan’s film, Panic in the Streets, and Neil Jordan’s cinematic interpretation of Interview with the Vampire.