We investigated a multistate outbreak of Escherichia coli O157:H7 infections. Isolates from 13 case patients from California, Nevada, and Arizona were matched by pulsed-field gel electrophoresis subtyping. Five case patients (38%) were hospitalized, and 3 (23%) developed hemolytic uremic syndrome; none died. The median age was 12 years (range, 2–75 years), and 10 (77%) were female. Case-control studies found an association between illness and eating beef tacos at a national Mexican-style fast-food restaurant chain (88% of cases versus 38% of controls; matched OR, undefined; 95% confidence interval, 1.49 to infinity; P = .009). A traceback investigation implicated an upstream supplier of beef, but a farm investigation was not possible. This outbreak illustrates the value of employing hospital laboratory-based surveillance to detect local clusters of infections and the effectiveness of using molecular subtyping to identify geographically dispersed outbreaks. The outbreak investigation also highlights the need for a more efficient tracking system for food products.