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Almost half of new HIV infections worldwide occur in women, and vaginal intercourse is the most common mode of transmission. Accumulating evidence suggests that depot medroxyprogesterone acetate may increase HIV transmission, but little is known about the underlying mechanisms. We propose that hypoestrogenism in depot medroxyprogesterone acetate may contribute to increased HIV transmission. We present supportive evidence and propose potential interventions to prevent or treat vaginal hypoestrogenism using vaginal estrogens.