This study investigated the efficacy of a 10-session, HIV-risk-reduction intervention with 221 women and 187 men receiving outpatient psychiatric care for a mental illness. Patients were randomly assigned to the HIV intervention, a structurally equivalent substance use reduction (SUR) intervention, or standard care; they were assessed pre- and postintervention and at 3- and 6-month follow-ups. Patients receiving the HIV-risk-reduction intervention reported less unprotected sex, fewer casual sex partners, fewer new sexually transmitted infections, more safer sex communications, improved HIV knowledge, more positive condom attitudes, stronger condom use intentions, and improved behavioral skills relative to patients in the SUR and control conditions. Patients receiving the SUR intervention reported fewer total and casual sex partners compared with control patients. Exploratory analyses suggested that female patients and patients diagnosed with a major depressive disorder were more likely to benefit from the HIV-risk-reduction intervention.