Recent studies have reported an association between acid-suppressing drugs (histamine H2 receptor antagonists and proton pump inhibitors) and development of infectious gastroenteritis. We conducted a case-control study nested in a cohort of more than 170,000 ever-users of acid-suppressing drugs to examine the association between acid-suppressing drugs and bacterial gastroenteritis, using data from the General Practice Research Database in the United Kingdom. We identified 374 confirmed cases of bacterial gastroenteritis and 2,000 randomly sampled controls from the study cohort. There was little increased risk of bacterial gastroenteritis among users of acid-suppressing drugs [relative risk (RR) = 1.1; 95% confidence interval (CI) = 0.8-1.4]. Omeprazole "single users" had an RR of 1.6 (95% CI = 1.0-2.4), but this effect was not observed among those using only omeprazole during the last year (RR = 1.1; 95% CI = 0.7-1.9). We did not find any dose or treatment duration response. These data do not support a major role for acid reduction in the development of bacterial gastroenteritis.