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.