Risk factors for Escherichia coli O157:H7 infection were investigated in a case-control study at 10 medical centers throughout the United States. Among 73 case-patients and 142 matched controls, exposures in the 7 days before illness associated with E. coli O157:H7 infection in univariate analysis included consumption of hamburger (matched odds ratio [MOR], 3.8; 95% confidence interval [CI], 1.9-7.9), undercooked hamburger (MOR, 4.5; 95% CI, 1.6-12.2), or hot dogs (MOR, 2.2; 95% CI, 1.1-4.4); eating at a fast-food restaurant (MOR, 2.3; 95% CI, 1.1-4.6); drinking unchlorinated well water (MOR, 2.4; 95% CI, 1.1-5.7); swimming in a pond (MOR, 5.4; 95% CI, 1.1-26.0); and having a household member with diarrhea (MOR, 11.9; 95% CI, 2.7-53.5). In multivariate analysis, only eating undercooked hamburger remained associated with infection. Seven (8%) of 93 patients developed hemolytic uremic syndrome and 1 died. Prevention strategies aimed at modifying risk factors may help to reduce the risk of infection with E. coli O157:H7.