In settings with low seroprevalence, people with severe mental illness have a higher prevalence of HIV infection compared to the general population. In the high-prevalence countries of southern Africa, where the pandemic taxes resources for HIV prevention, care, and treatment, the needs of people with mental illness can be easily overlooked if they are not identified as vulnerable to infection. Yet, few African studies have investigated HIV seroprevalence in psychiatric settings. We systematically examined the HIV seroprevalence among psychiatric patients admitted to a public psychiatric institution in KwaZulu Natal province, South Africa, between 27 July and 14 November 2003. We conducted anonymous testing among 151 patients who were psychiatrically stable and able to give informed consent. Forty patients (26.5%) were HIV-positive; women were more likely to be infected than men (OR 2.74; 95% CI=1.25-6.04; P=0.012). Our findings demonstrate that in the midst of a generalized AIDS epidemic, people with mental illness are also vulnerable and must be included in prevention and treatment efforts. These results underscore the importance of integrated mental health and HIV care in institutional and outpatient mental health settings and affirm the need for detailed HIV risk assessment as a routine part of psychiatric care. Correspondingly, HIV care and treatment programs should be made available to people with psychiatric symptoms.