BACKGROUND: The relationship of loop diuretics to bone mineral density (BMD), falls, and fractures in postmenopausal women has not been established. METHODS: We examined whether loop diuretics are associated with changes in BMD, falls, and fractures in women enrolled in the Women's Health Initiative. We included the 133,855 women (3411 users and 130,444 nonusers of loop diuretics) who were enrolled in the WHI from October 29, 1993 to December 31, 1998 and determined incident falls and fractures for a mean of 7.7 years. Women who had BMD measurements at baseline and at year 3 (300 users and 9124 nonusers of loop diuretics) were also examined. RESULTS: After adjustment for covariates, no significant association was found between ever use of loop diuretics and total (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.00-1.19), hip (HR, 1.21; 95% CI, 0.91-1.60), and clinical vertebral fractures (HR, 1.17; 95% CI, 0.92-1.48) and falls (1.02; 0.96-1.08). An increased risk was found for other clinical fractures (1.16; 1.01-133) and total fractures (1.16; 1.03-1.31) with more than 3 years' use of loop diuretics. The BMD changes were not associated with loop diuretic use. CONCLUSIONS: After adjustment for confounding variables, no significant association was found between ever use of loop diuretics and changes in BMD, falls, and fractures. Loop diuretics were used by women in poor health who were already at risk for fractures. However, prolonged use of loop diuretics was associated with higher fracture risk in postmenopausal women.