The 1878 Mississippi Valley yellow fever outbreak was one of the worst disasters in US history. During the epidemic, quarantines attempted to thwart the spread of the disease. Quarantines, however, not only limited the movement of people and goods but also threatened the flow of information. This article explores the epidemic's impact on postal communication. A close examination of the outbreak highlights the ongoing importance of postal communication in the United States during the late nineteenth century, and it foregrounds the importance of a set of overlooked informational practices—"postal disinfection"—that were essential to maintaining complex communication networks during periods of epidemics.