BackgroundPreexposure prophylaxis (PrEP) with antiretroviral drugs may prevent transmission of human immunodeficiency virus (HIV). Our objective was to predict whether PrEP, in the presence of circulating drug resistance, will reduce the risk of infection with HIV MethodsWe used risk equations to calculate the monthly risk of infection with HIV before and after the introduction of PrEP. Uncertainty and sensitivity analyses were performed for 2 ranges of PrEP effectiveness (40%–60% and 60%–80%). Circulating drug resistance was assumed to reduce the effectiveness of PrEP by 50%–90% and the transmissibility of HIV by 0%–30%. Parameter ranges were chosen for women 17–29 years of age from publications on HIV in Manicaland in Zimbabwe ResultsPrEP would decrease the median risk of HIV transmission by 21%–33% (effectiveness of PrEP, 40%–60% and 60%–80%). If 50% of HIV strains are drug resistant, then the median risk reduction would be 19%–26% if drug-resistant strains were less transmissible than wild-type HIV and 12%–19% if they were equally transmissible. The risk would increase if condoms were frequently replaced with PrEP. Use of PrEP for sexual acts for which no protection is currently used would be beneficial ConclusionThe public health impact of PrEP will depend on its effectiveness and on risk behavior. Circulating drug resistance will have only a small impact on the effectiveness of PrEP