Substance-using men who have sex with men (MSM) are among the groups at highest risk for HIV infection in the United States. We report the results of a randomized trial testing the efficacy of a small group sexual and substance use risk reduction intervention based on empowerment theory compared to an enhanced efficacious control condition among 515 high risk not-in-treatment MSM substance users. Effect sizes for sexual risk and substance use outcomes were moderate to large: HIV transmission risk frequency, d = 0.71 in the control versus 0.66 in the experimental group; number of anal sex partners, d = 1.04 versus 0.98; substance dependence symptoms, d = 0.49 versus 0.53; significant differences were not observed between conditions. Black MSM reduced their risks at a greater rate than White or Latino men. The findings point to a critically important research agenda to reduce HIV transmission among MSM substance users.