BACKGROUND & AIMS: Drugs that inhibit gastric acid might increase the risk of hip fracture. However, little long-term exposure data exist and no large studies have been conducted in the United States. METHODS: We conducted a case-control study using data from an integrated health services organization. We evaluated 33,752 patients with incident diagnoses of hip/femur fractures (cases), 130,471 matched members without fractures (controls), prescription data for use of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) (up to 10 years’ cumulative duration), and confounders. RESULTS: Patients with hip fractures were more likely than controls to have previously received a > or =2-year supply of PPIs (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.21-1.39) or H2RAs (OR, 1.18; 95% CI, 1.08-1.29). The risk was reduced after discontinuation of medication (OR of 1.30 [95% CI, 1.21-1.41] for current PPI users vs OR of 1.09 [95% CI, 0.64-1.85] for patients who received their last prescription 2-2.9 years ago). Higher dosages (but not increasing cumulative durations) were associated with increased risk (eg, > or =1.5 pills/day: OR, 1.41 [95% CI, 1.21-1.64]; <0.74 pills/day: OR, 1.12 [95% CI, 0.94-1.33]). Excess fracture risk for PPI use was only present among persons with at least one other fracture risk factor. CONCLUSIONS: Use of drugs that inhibit gastric acid is associated with an increased risk of hip fracture; however, this association was only found among persons with at least one other risk factor for hip fracture. Acid inhibition might therefore be associated with fracture risk in persons already at risk for osteoporosis, although other confounding cannot be excluded.