Daily oral dosing of the antiretroviral drugs tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) has been approved by the FDA pre-exposure prophylaxis (PrEP). Oral PrEP has been shown to be highly effective in preventing HIV transmission through the rectum, but less effective, and in some studies ineffective, in preventing vaginal transmission. Determinants of tissue penetration of antiretroviral drugs are not well understood and may be partially explained by differences in sex hormones. This is a biphasic steady state pharmacokinetic and pharmacodynamic study of approximately 16 healthy women to evaluate the impact of depot medroxyprogesterone acetate (DMPA) on concentrations of TDF and FTC in the blood, lower genital tract, and rectum. TDF and FTC drug concentrations will be assessed at steady state both before and after DMPA administration, and HIV challenge assays will also be performed with fresh cervical tissues before any study drug, after TDF and FTC only, and again when TDF, FTC, and DMPA are administered concommitantly. Factors that change the dynamics of PrEP drugs in the female genital tract even minimally could have a significant impact on drug effectiveness and thus on HIV susceptibility in at-risk women.