The purpose of this clinical trial was to evaluate the effect of estrogen supplementation on bone mineral density in adolescent girls who received depot medroxyprogesterone acetate for contraception. One hundred twenty- three adolescents who began receiving depot medroxyprogesterone acetate injections every 12 weeks were assigned randomly to receive monthly injections of estradiol cypionate or placebo. The main outcome was bone mineral density that was measured by dual energy x- ray absorptiometry for 12 (n = 69) to 24 (n = 36) months. Participants, technicians, and physicians were blinded to estrogen treatment. Over the 24- month period, the percentage of change from baseline bone mineral density at the lumbar spine was 2.8% in the estradiol cypionate group versus - 1.8% in the placebo group (P <.001). At the femoral neck, the percentage of change from baseline bone mineral density was 4.7% in the estradiol cypionate group versus - 5.1% in the placebo group (P <.001). Our results suggest that estrogen supplementation is protective of bone in adolescent girls who receive depot medroxyprogesterone acetate injections. The purpose of this clinical trial was to evaluate the effect of estrogen supplementation on bone mineral density in adolescent girls who received depot medroxyprogesterone acetate for contraception. One hundred twenty- three adolescents who began receiving depot medroxyprogesterone acetate injections every 12 weeks were assigned randomly to receive monthly injections of estradiol cypionate or placebo. The main outcome was bone mineral density that was measured by dual energy x-ray absorptiometry for 12 (n = 69) to 24 (n = 36) months. Participants, technicians, and physicians were blinded to Over the 24- month period, the percentage of change from baseline bone mineral density at the lumbar spine was 2.8% in the estradiol cypionate group versus - 1.8% in the placebo group (P <.001). At the femoral neck , the percentage of change from baseline bone mineral density was 4.7% in the estradiol cypionate group versus - 5.1% in the placebo group (P <.001). Our results sugg est that estrogen supplementation is protective of bone in adolescent girls who receive depot medroxyprogesterone acetate injections.