People living with a mental illness are disproportionately vulnerable to human immunodeficiency virus. The current study sought to examine the influence of psychiatric disorder, substance use disorder, and gender on risky sexual behavior in this vulnerable population. Participants were 228 female and 202 male outpatients (66% mood disorder, 34% schizophrenia), each of whom took part in a Structured Clinical Interview for the DSM-IV and a comprehensive assessment of sexual risk behavior. Univariate and multivariate analyses tested a priori hypotheses. The results indicated that risk behavior was more frequent among patients diagnosed with a mood disorder (compared with those diagnosed with schizophrenia) or a substance use disorder (compared with those without a comorbid disorder) or both. We recommend routine human immunodeficiency virus risk screening and risk reduction programs for this vulnerable population.