A large outbreak of the hemolytic-uremic syndrome caused by Shiga-toxin-producing Escherichia coli O104:H4 occurred in Germany in May 2011. The source of infection was undetermined. We conducted a matched case-control study and a recipe-based restaurant cohort study, along with environmental, trace-back, and trace-forward investigations, to determine the source of infection. The case-control study included 26 case subjects with the hemolytic-uremic syndrome and 81 control subjects. The outbreak of illness was associated with sprout consumption in univariable analysis (matched odds ratio, 5.8; 95% confidence interval [CI], 1.2 to 29) and with sprout and cucumber consumption in multivariable analysis. Among case subjects, 25% reported having eaten sprouts, and 88% reported having eaten cucumbers. The recipe-based study among 10 groups of visitors to restaurant K included 152 persons, among whom bloody diarrhea or diarrhea confirmed to be associated with Shiga-toxin-producing E. coli developed in 31 (20%). Visitors who were served sprouts were significantly more likely to become ill (relative risk, 14.2; 95% CI, 2.6 to ∞). Sprout consumption explained 100% of cases. Trace-back investigation of sprouts from the distributor that supplied restaurant K led to producer A. All 41 case clusters with known trading connections could be explained by producer A. The outbreak strain could not be identified on seeds from the implicated lot. Our investigations identified sprouts as the most likely outbreak vehicle, underlining the need to take into account food items that may be overlooked during subjects' recall of consumption.