Several strains of multidrug-resistant (MDR) Salmonella serotype Typhimurium, including MDR S. Typhimurium definitive type 104, cause almost 10% of Salmonella infections among humans in the United States. To determine the risk factors for acquiring sporadic MDR S. Typhimurium infection, we conducted a population-based, case-control study using data from the Foodborne Diseases Active Surveillance Network (FoodNet) during 1996-1997. S. Typhimurium isolates from 5 FoodNet surveillance areas (California, Connecticut, Georgia, Minnesota, and Oregon) were tested for antimicrobial resistance and phage typing. Telephone interviews were conducted with ill persons and matched control subjects. Compared with both control subjects and patients infected with pansensitive strains of S. Typhimurium, patients with MDR S. Typhimurium infection were significantly more likely to have received an antimicrobial agent, particularly an agent to which the Salmonella isolate was resistant, during the 4 weeks preceding illness onset. Prudent antimicrobial agent use among humans and among veterinarians and food-animal producers is necessary to reduce the burden of drug-resistant salmonellosis in humans.