Proton pump inhibitor (PPI) medications have been inconsistently shown to be associated with osteoporotic fractures. We examined the association of PPI use with bone outcomes (fracture, bone mineral density [BMD]).This prospective analysis included 161 806 postmenopausal women 50 to 79 years old, without history of hip fracture, enrolled in the Women's Health Initiative (WHI) Observational Study and Clinical Trials with a mean (SD) follow-up of 7.8 (1.6) years. Analyses were conducted for 130 487 women with complete information. Medication information was taken directly from drug containers during in-person interviews (baseline, year 3). The main outcome measures were self-reported fractures (hip [adjudicated], clinical spine, forearm or wrist, and total fractures) and for a subsample (3 densitometry sites), 3-year change in BMD.During 1 005 126 person-years of follow-up, 1500 hip fractures, 4881 forearm or wrist fractures, 2315 clinical spine fractures, and 21 247 total fractures occurred. The multivariate-adjusted hazard ratios for current PPI use were 1.00 (95% confidence interval [CI], 0.71-1.40) for hip fracture, 1.47 (95% CI, 1.18-1.82) for clinical spine fracture, 1.26 (95% CI, 1.05-1.51) for forearm or wrist fracture, and 1.25 (95% CI, 1.15-1.36) for total fractures. The BMD measurements did not vary between PPI users and nonusers at baseline. Use of PPIs was associated with only a marginal effect on 3-year BMD change at the hip (P = .05) but not at other sites.Use of PPIs was not associated with hip fractures but was modestly associated with clinical spine, forearm or wrist, and total fractures.