Recent studies have suggested an increased fracture risk with acid-suppressive medication use. We studied two cohorts of men and women over age 65 who were enrolled in the Osteoporotic Fractures in Men Study (MrOS) and the Study of Osteoporotic Fractures (SOF), respectively. We used dual-energy X-ray absorptiometry and assessed baseline use of proton pump inhibitors (PPIs) and/or H2 receptor antagonists (H2RAs) in 5,755 men and 5,339 women. Medication use and bone mineral density (BMD) were assessed, and hip and other nonspine fractures were documented. On multivariate analysis, men using either PPIs or H2RAs had lower cross-sectional bone mass. No significant BMD differences were observed among women. However, there was an increased risk of nonspine fracture among women using PPIs (relative hazard [RH] = 1.34, 95% confidence interval [CI] 1.10-1.64). PPI use was also associated with an increased risk of nonspine fracture in men but only among those who were not taking calcium supplements (RH = 1.49, 95% CI 1.04-2.14). H2RA use was not associated with nonspine fractures, and neither H2RA use nor PPI use was associated with incident hip fractures in men or women. The use of PPIs in older women, and perhaps older men with low calcium intake, may be associated with a modestly increased risk of nonspine fracture.