Background. Escherichia coli O157:H7 is the leading cause of hemolytic uremic syndrome (HUS). Risk factors for development of this complication warrant identification.Methods.We enrolled children infected with E. coli O157:H7 within 1 week of the onset of diarrhea in this prospective cohort study. The study was conducted in 5 states over 9.5 years. The primary and secondary outcomes were HUS (hematocrit <30 with smear evidence of hemolysis, platelet count <150 × 103/L, and serum creatinine concentration > upper limit of normal for age) and oligoanuric HUS. Univariate and multivariable and ordinal multinomial regression analyses were used to test associations between factors apparent during the first week of illness and outcomes.Results.Of the 259 children analyzed, 36 (14) developed HUS. Univariate analysis demonstrated that children who received antibiotics during the diarrhea phase more frequently developed HUS than those who did not (36 vs 12; P =. 001). The higher rate of HUS was observed across all antibiotic classes used. In multivariable analysis, a higher leukocyte count (adjusted odds ratios [aOR] 1.10; 95 CI, 1.03-1.19), vomiting (aOR 3.05; 95 CI, 1.23-7.56), and exposure to antibiotics (aOR 3.62; 95 CI, 1.23-10.6) during the first week of onset of illness were each independently associated with development of HUS. Multinomial ordinal logistic regression confirmed that initial leukocyte count and antibiotic use were independently associated with HUS and, additionally, these variables were each associated with the development of oligoanuric HUS.Conclusions.Antibiotic use during E. coli O157:H7 infections is associated with a higher rate of subsequent HUS and should be avoided.