Background: Acid-suppressive medications are increasingly prescribed for noncritically ill hospitalized patients, although the incidence of nosocomial gastrointestinal (GI) tract bleeding (GI bleeding) and magnitude of potential benefit from this practice are unknown. We aimed to define the incidence of nosocomial GI bleeding outside of the intensive care unit and examine the association between acid-suppressive medication use and this complication. Methods: We conducted a pharmacoepidemiologic cohort study of patients admitted to an academic medical center from 2004 through 2007, at least 18 years of age, and hospitalized for 3 or more days. Admissions with a primary diagnosis of GI bleeding were excluded. Acid-suppressive medication use was defined as any order for a proton pump inhibitor or histamine-2-receptor antagonist. The main outcome measure was nosocomial GI bleeding. A propensity matched generalized estimating equation was used to control for confounders. Results:The final cohortincluded 78 394 admissions (median age, 56 years; 41% men). Acid-suppressive medication was ordered in 59% of admissions, and nosocomial GI bleeding occurred in 224 admissions (0.29%). After matching on the propensity score, the adjusted odds ratio for nosocomial GI bleeding in the group exposed to acid-suppressive medication relative to the unexposed group was 0.63 (95% confidence interval, 0.42-0.93). The number needed to treat to prevent 1 episode of nosocomial GI bleeding was 770. Conclusions: Nosocomial GI bleeding outside of the intensive care unit was rare. Despite a protective effect of acid-suppressive medication, the number needed to treat to prevent 1 case of nosocomial GI bleeding was relatively high, supporting the recommendation against routine use of prophylactic acid-suppressive medication in noncritically ill hospitalized patients.