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Background The spread of human immunodeficiency virus infection to impaired groups has intensified the challenge for its prevention; control of the epidemic now requires behavioral change among persons with limited ability to sustain attention and learn. In this randomized clinical trial, we tested an intervention to reduce sexual risk behaviors among homeless men with severe mental illness. Methods Men were recruited from a psychiatric program in a homeless shelter. Of 116 eligible men, 97 (83.6%) participated. Most were African American and had a chronic psychotic disorder and a comorbid substance use disorder. Participants were assigned to a 15-session experimental group intervention or to a 2-session control intervention and observed for 18 months. The 59 participants sexually active before the trial were the main target of the intervention. Sexual risk behavior was the primary outcome. Results Among the 59 sexually active men, follow-up data were obtained on 59 (100%) for the initial 6-month follow-up and on 56 (95%) for the remainder of the 18-month follow-up. The mean score on a sexual risk index for the experimental group was 3 times lower than for the control group (1.0 vs 3.1; P =.01) during the initial 6-month follow-up and 2 times lower during the remainder of the 18-month follow-up. Conclusions This intervention successfully reduced sexual risk behaviors of homeless men with mental illness. The effect diminished over 18 months but did not disappear. Similar approaches may be effective in other impaired high-risk groups.