Two waves of antimicrobial-resistant Salmonella typhimurium infections in Illinois totaling over 16 000 culture-confirmed cases were traced to two brands of pasteurized 2% milk produced by a single dairy plant. Salmonellosis was associated with taking antimicrobials before onset of illness. Two surveys to determine the number of persons who were actually affected yielded estimates of 168 791 and 197 581 persons, making this the largest outbreak of salmonellosis ever identified in the United States. The epidemic strain was easily identified because it had a rare antimicrobial resistance pattern and a highly unusual plasmid profile; study of stored isolates showed it had caused clusters of salmonellosis during the previous ten months that may have been related to the same plant, suggesting that the strain had persisted in the plant and repeatedly contaminated milk after pasteurization.