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Promising multi-dose HIV vaccine regimens are being tested in trials in South Africa. We estimated the potential epidemiological and economic impact of HIV vaccine campaigns compared to continuous vaccination, assuming that vaccine efficacy is transient and dependent on immune response. We used a dynamic economic mathematical model of HIV transmission calibrated to 2012 epidemiological data to simulate vaccination with anticipated antiretroviral treatment scale-up in South Africa. We estimate that biennial vaccination with a 70% efficacious vaccine reaching 20% of the sexually active population could prevent 480,000–650,000 HIV infections (13.8–15.3% of all infections) over 10 years. Assuming a launch price of $15 per dose, vaccination was found to be cost-effective, with an incremental cost-effectiveness ratio of $13,746 per quality-adjusted life-year as compared to no vaccination. Increasing …