Objective: To determine factors possibly associated with reduced bone density in women using the injectable contraceptive depot medroxyprogesterone acetate. Methods: In a cross-sectional study, bone mineral density of the lumbar spine was measured by dual energy x-ray absorptiometry in 200 current users of depot medroxyprogesterone acetate who had used this method of contraception for 2-26 years and compared with 350 control subjects. Bone density results are expressed as standard deviation scores (z score). Results: The bone density was significantly lower in depot medroxyprogesterone acetate users (mean z score: -0.65, 95% confidence intervals [CI] -0.80, -0.49, P < .001). Bone density was significantly reduced in nonsmokers and smokers, and there was no significant difference in mean z score between smokers and nonsmokers (mean -0.75 versus -0.58, P = .30). Women who had started depot medroxyprogesterone acetate after the age of 20 years and who had used it for 15 or fewer years had a significantly higher bone density than the remainder of the cohort (mean -0.45 [95% CI -0.62, -0.27] versus -1.02 [95% CI -1.32, -0.73], P < .005). Bone density in depot medroxyprogesterone acetate users was not related to current age, parity, body mass index, calcium intake, or exercise. Conclusion: Depot medroxyprogesterone acetate use is associated with a significant reduction in bone density, and although a high proportion of depot medroxyprogesterone users do smoke, the reduction in bone density cannot be explained by smoking. Women who use it for a long time and those who start it before peak bone mass is attained may be at highest risk. (Obstet Gynecol 1998;92:569-73. (C) 1998 by The American College of Obstetricians and Gynecologists.).