BACKGROUND The impact of antiretroviral therapy (ART) on sexual risk behavior and HIV transmission among HIV-infected persons in Africa is unknown. OBJECTIVE To assess changes in risky sexual behavior and estimated HIV transmission from HIV-infected adults after 6 months of ART. DESIGN AND METHODS A prospective cohort study was performed in rural Uganda. Between May 2003 and December 2004 a total of 926 HIV-infected adults were enrolled and followed in a home-based ART program that included prevention counselling, voluntary counseling and testing (VCT) for cohabitating partners and condom provision. At baseline and follow-up, participants' HIV plasma viral load and partner-specific sexual behaviors were assessed. Risky sex was defined as inconsistent or no condom use with partners of HIV-negative or unknown serostatus in the previous 3 months. The rates of risky sex were compared using a Poisson regression model and transmission risk per partner was estimated, based on established viral load-specific transmission rates. RESULTS Six months after initiating ART, risky sexual behavior reduced by 70% [adjusted risk ratio, 0.3; 95% confidence interval (CI), 0.2-0.7; P = 0.0017]. Over 85% of risky sexual acts occurred within married couples. At baseline, median viral load among those reporting risky sex was 122 500 copies/ml, and at follow-up, < 50 copies/ml. Estimated risk of HIV transmission from cohort members declined by 98%, from 45.7 to 0.9 per 1000 person years. CONCLUSIONS Providing ART, prevention counseling, and partner VCT was associated with reduced sexual risk behavior and estimated risk of HIV transmission among HIV-infected Ugandan adults during the first 6 months of therapy. Integrated ART and prevention programs may reduce HIV transmission in Africa.