Community-randomized trials in Mwanza, Tanzania, and Rakai and Masaka, Uganda, suggested that population characteristics were an important determinant of the impact of sexually transmitted infection (STI) treatment interventions on incidence of human immunodeficiency virus (HIV) infection. We performed simulation modeling of HIV and STI transmission, which confirmed that the low trial impact in Rakai and Masaka could be explained by low prevalences of curable STI resulting from lower-risk sexual behavior in Uganda. The mature HIV epidemics in Uganda, with most HIV transmission occurring outside core groups with high STI rates, also contributed to the low impact on HIV incidence. Simulated impact on HIV was much greater in Mwanza, although the observed impact was larger than predicted from STI reductions, suggesting that random error also may have played some role. Of proposed alternative explanations, increasing herpetic ulceration due to HIV-related immunosuppression contributed little to the diminishing impact of antibiotic treatment during the Ugandan epidemics. The strategy of STI treatment also was unimportant, since syndromic treatment and annual mass treatment showed similar effectiveness in simulations of each trial population. In conclusion, lower-risk behavior and the mature HIV epidemic explain the limited impact of STI treatment on HIV incidence in Uganda in the 1990s. In populations with high-risk sexual behavior and high STI rates, STIs treatment interventions may contribute substantially to prevention of HIV infection.