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A synergy between HIV and herpes simplex virus type 2 (HSV-2) infections has been reported in observational studies. The objectives of this study were to estimate the per-sex-act female-to-male transmission probabilities (FtoMTPs) of HIV and HSV-2, the effect of each infection on the FtoMTP of the other and the effect of male circumcision on these FtoMTPs.We used longitudinal data collected during the male circumcision trial conducted in Orange Farm (South Africa).Results were obtained by specific mathematical modeling of HIV and HSV-2 statuses of the men as functions of their sexual behavior and male circumcision status. The model took into account an estimation of the HIV and HSV-2 statuses of each of their female partners. Confidence intervals (CI) were estimated using a bootstrap re-sampling method.The HIV and HSV-2 FtoMTPs, during an unprotected sexual contact for an uncircumcised male in the absence of the other virus in both partners, were 0.0047 (95% CI: 0.0014–0.017) and 0.0067 (95% CI: 0.0028–0.014), respectively. HSV-2 in either partner increased HIV FtoMTP with a relative risk (RR) of 3.0 (95% CI: 1.01–7.3). Conversely, HIV in either partner increased HSV-2 FtoMTP (RR = 2.5; 95% CI: 1.1–6.3). Male circumcision significantly decreased these probabilities with RRs of 0.24 (95% CI: 0.11–0.44) and 0.59 (95% CI: 0.36–0.91), respectively.This study gave the first estimates of HSV-2 per-sex-act FtoMTPs in Africa. It demonstrated a synergy between HIV and HSV-2 infections and a protective effect of male circumcision on HSV-2 acquisition by males.