A prospective cohort study of 3381 African heterosexual HIV-1 serodiscordant couples found that initiating antiretroviral therapy (ART) significantly reduced the risk of HIV-1 transmission. Among HIV-1 infected partners who initiated ART, the risk of transmission was reduced by 92% compared to those who did not. This reduction was primarily due to a significant decrease in plasma HIV-1 RNA levels, which dropped from a median of 4.88 to less than 2.38 log10 copies/mL after ART initiation. Additionally, there was a decrease in unprotected sex, from 6.2% to 3.7% of visits. The highest transmission risk was observed in couples where the HIV-1 infected partner had CD4 counts below 200 cells/mm³ or plasma HIV-1 RNA concentrations above 50,000 copies/mL. In these cases, ART provided the greatest relative prevention benefit. The study also found that ART initiation was associated with increased self-reported condom use. The findings support the use of ART as a prevention strategy, particularly for individuals with high viral loads and low CD4 counts. The study highlights the importance of ART in reducing HIV-1 transmission and emphasizes the need for targeted ART provision to those at highest risk. The results are consistent with previous meta-analyses and suggest that ART can significantly reduce HIV-1 transmission risk. The study also underscores the importance of ongoing research to understand the long-term benefits and risks of ART in HIV-1 prevention.A prospective cohort study of 3381 African heterosexual HIV-1 serodiscordant couples found that initiating antiretroviral therapy (ART) significantly reduced the risk of HIV-1 transmission. Among HIV-1 infected partners who initiated ART, the risk of transmission was reduced by 92% compared to those who did not. This reduction was primarily due to a significant decrease in plasma HIV-1 RNA levels, which dropped from a median of 4.88 to less than 2.38 log10 copies/mL after ART initiation. Additionally, there was a decrease in unprotected sex, from 6.2% to 3.7% of visits. The highest transmission risk was observed in couples where the HIV-1 infected partner had CD4 counts below 200 cells/mm³ or plasma HIV-1 RNA concentrations above 50,000 copies/mL. In these cases, ART provided the greatest relative prevention benefit. The study also found that ART initiation was associated with increased self-reported condom use. The findings support the use of ART as a prevention strategy, particularly for individuals with high viral loads and low CD4 counts. The study highlights the importance of ART in reducing HIV-1 transmission and emphasizes the need for targeted ART provision to those at highest risk. The results are consistent with previous meta-analyses and suggest that ART can significantly reduce HIV-1 transmission risk. The study also underscores the importance of ongoing research to understand the long-term benefits and risks of ART in HIV-1 prevention.