Salmonella Javiana is a Salmonella serotype that is restricted geographically in the United States to the Southeast. During the summer of 2001, the number of reported S. Javiana infections in Mississippi increased sevenfold. To identify sources of infection, we conducted a case-control study, defining a case as an infection with S. Javiana between August and September in a Mississippi resident. We enrolled 55 cases and 109 controls. Thirty (55%) case patients reported exposure to amphibians, defined as owning, touching, or seeing an amphibian on one's property, compared with 30 (29%) controls (matched odds ratio 2·8, P=0·006). Contact with amphibians and their environments may be a risk factor for human infection with S. Javiana. The geographic pattern of S. Javiana infections in the United States mimics the distribution of certain amphibian species in the Southeast. Public health officials should consider amphibians as potential sources of salmonellosis, and promote hand washing after contact with amphibians.