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To model the effect of health systems performance on rates of mother-to-child HIV transmission.We modeled the effect of variation in performance of the multiple steps of different prevention of mother-to-child transmission (PMTCT) protocols using hypothetical and reported data.Data from a PMTCT program in a large province in South Africa was used to compare model predictions with reported outcomes for mother-to-child HIV transmission.Perinatal HIV transmission was predicted for infants of 6 weeks of age.HIV-infected pregnant women who fulfill eligibility criteria are initiated on lifelong antiretroviral treatment, whereas noneligible HIV-infected women and their infants receive single-dose nevirapine in a health system functioning at reported performance levels, and the overall vertical transmission rate would be 19.5%. Adding azidothymidine for women not eligible for lifelong treatment would further decrease the overall transmission rates only marginally to 17%. If the same steps were accomplished at 95% reliability, then the overall transmission rates would be 9.4% and 4.1%, respectively.Introduction of more effective combination antiretroviral interventions will yield only marginal reductions in childhood HIV infections and mortality unless health systems achieve high levels of performance at each step of the PMTCT pathway. Investment in and support for the mechanisms of delivering and sustaining PMTCT interventions at scale are required if gains in maternal and child survival are to be realized in countries highly affected by HIV.