['Epidemiologic studies remain inconclusive on whether the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) increases mucosal HIV shedding and transmissibility. Nonhuman primate models may help to determine the effects of DMPA on acute HIV replication.', 'We defined a physiologic dose of DMPA in macaques and assessed the impact of DMPA on acute simian HIV (SHIV) replication.', 'Pigtail macaques received 1-30 \u200amg of DMPA intramuscularly followed by measurements of progesterone and medroxyprogesterone acetate (MPA). Vaginal epithelial thickness, number of cell layers and density of intraepithelial CD3 cells were measured. The effect of DMPA on SHIV viremia and genital virus shedding was investigated in six pigtail macaques infected during monthly treatment cycles with 3 \u200amg DMPA. Six DMPA-untreated macaques were controls.', 'Plasma MPA concentrations directly correlated with changes in epithelial thickness (correlation = 0.84; P < 0.001) and density of intraepithelial CD3 cells (correlation = 0.41; P = 0.02). A 3 mg DMPA dose recapitulated plasma MPA concentrations and changes in vaginal epithelial thickness seen in women. DMPA-treated and untreated macaques showed similar peak plasma viremia and RNA area under the curve values over 12 weeks (P = 0.94), although treated macaques had higher odds of having virus being detected in plasma (odds ratio 6.6, P = 0.02). Rectal and vaginal virus shedding was similar between treated and untreated macaques (P \u200a= 0.72 and P = 0.53, respectively).'] Do physiologic doses of depot-medroxyprogesterone acetate increase acute plasma simian HIV viremia or mucosal virus shedding in pigtail macaques?