The efficacy of a behavioral intervention to reduce human immunodeficiency virus (HIV) risk behaviors was tested in a randomized, controlled trial with three high-risk populations at 37 clinics from seven sites across the United States. Compared with the 1855 individuals in the control condition, the 1851 participants assigned to a small-group, seven-session HIV risk reduction program reported fewer unprotected sexual acts, had higher levels of condom use, and were more likely to use condoms consistently over a 12-month follow-up period. On the basis of clinical record review, no difference in overall sexually transmitted disease (STD) reinfection rate was found between intervention and control condition participants. However, among men recruited from STD clinics, those assigned to the intervention condition had a gonorrhea incidence rate one-half that of those in the control condition. Intervention condition participants also reported fewer STD symptoms over the 12-month follow-up period. Study outcomes suggest that behavioral interventions can reduce HIV-related sexual risk behavior among low-income women and men served in public health settings. Studies that test strategies for reducing sexual risk behavior over longer periods of time are needed, especially with populations that remain most vulnerable to HIV infection.