A multistate outbreak of Escherichia coli O157:H7 infections occurred in the USA in November–December 2006 in patrons of restaurant chain A. We identified 77 cases with chain A exposure in four states – Delaware, New Jersey, New York, and Pennsylvania. Fifty-one (66%) patients were hospitalized, and seven (9%) developed haemolytic uraemic syndrome; none died. In a matched analysis controlling for age in 31 cases and 55 controls, illness was associated with consumption of shredded iceberg lettuce [matched odds ratio (mOR) 8·0, 95% confidence interval (CI) 1·1–348·1] and shredded cheddar cheese (mOR 6·2, CI 1·7–33·7). Lettuce, an uncooked ingredient, was more commonly consumed (97% of patients) than cheddar cheese (84%) and a single source supplied all affected restaurants. A single source of cheese could not explain the regional distribution of outbreak cases. The outbreak highlights challenges in conducting rapid multistate investigations and the importance of incorporating epidemiological study results with other investigative findings.