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AbstractIntroductionSome observational data suggest that the progestogen injectable contraceptive depot medroxyprogesterone acetate (DMPA) may increase a woman's risk of HIV acquisition but a randomized clinical trial did not find a statistically significant increase in HIV risk for women using DMPA compared to two other methods. However, it could not rule out up to 30% increased HIV risk for DMPA users. We evaluate changes to contraceptive method mix in South Africa under different assumptions about the existence and strength of a possible undetected relationship between DMPA use and HIV risk.MethodsA mathematical model was developed to simulate the ongoing HIV epidemic and contraceptive method mix in South Africa to estimate how changes in method mix could impact HIV‐ and reproductive health‐related outcomes. We made different assumptions about the relationship between DMPA use and HIV risk, from no relationship to a 30% increase in HIV risk for women using DMPA. Scenario analyses were used to investigate the impact of switching away from DMPA predominance to new patterns of contraceptive use.ResultsIn South Africa, the HIV‐related benefits of reduced DMPA use could be as great as the harms of increased adverse reproductive health outcomes over 20 years, if DMPA did increase the risk of HIV acquisition by a relative hazard of infection of 1.1 or greater. A reduction in DMPA use among HIV‐positive women would have no benefit in terms of HIV infections, but would incur additional negative reproductive health outcomes. The most important driver of adverse reproductive health outcomes is the proportion of women who switch away from DMPA to no contraceptive method.ConclusionsIf there is any real increased HIV risk for DMPA users that has not been detected by the recent randomized trial, a reduction in DMPA use could reduce the ongoing number of new HIV infections. However, such a change would place more women at risk of adverse reproductive health effects. It is imperative that these effects are minimized by focusing on expanding access to safe, effective and acceptable alternative contraceptive methods for all women.