Prostaglandin inhibition by aspirin or nonsteroidal anti-inflammatory drug (NSAIDs) may inhibit bone loss and preserve bone mineral density (BMD) in vitro and in animal models. The effect of these agents on BMD and fracture risk in postmenopausal women in unknown. We assessed the risk factors for osteoporosis and the use of aspirin and NSAIDs in 7786 white women over age 65. Axial BMD was measured at the same time, and fractures were prospectively documented over the subsequent 4 years of follow-up. In age-adjusted analyses, daily use of aspirin or NSAIDs was associated with a 2.3-5.8% increase in BMD of the hip and spine. The relationship persisted even after adjustment for weight, a variety of medications, self-reported arthritis, and for radiographic findings of osteoarthritis, but the multiply adjusted increase in BMD was only 1.0-3.1%. Fracture risk was similar among daily users of aspirin and NSAIDs and nonusers. After adjustment for potential confounders, among daily aspirin users the relative risk of hip fracture was 1.1 (95% confidence interval [CI]: 0.7, 1.6), and among daily NSAID users the risk was 0.9 (CI: 0.6, 1.4). Considering all nonspine fractures together, the risk among aspirin users was 1.0 (CI: 0.8. 1.2), and among NSAID users the risk was also 1.0 (CI; 0.8, 1.2). Regular use of aspirin or NSAIDs may have a modest beneficial effect on BMD in postmenopausal women. This effect persists after adjustment for obesity and the presence of osteoarthritis. However, among women who take aspirin or NSAIDs regularly, there is no clinically significant protective effect on the subsequent risk of fractures.