Little is known about the impact of comorbid psychiatric symptoms in persons with HIV. This study estimates the burden on health-related quality of life associated with comorbid psychiatric conditions in a nationally representative sample of persons with HIV. The authors conducted a multistage sampling of urban and rural areas to produce a national probability sample of persons with HIV receiving medical care in the contiguous United States (N=2,864). Subjects were screened for psychiatric conditions with the short form of the Composite International Diagnostic Interview. Heavy drinking was assessed on the basis of quantity and frequency of drinking. Health-related quality of life was rated with a 28-item instrument adapted from similar measures used in the Medical Outcomes Study. HIV subjects with a probable mood disorder diagnosis had significantly lower scores on health-related quality of life measures than did those without such symptoms. Diminished health-related quality of life was not associated with heavy drinking, and in drug users it was accounted for by presence of a comorbid mood disorder. Optimization of health-related quality of life is particularly important now that HIV is a chronic disease with the prospect of long-term survival. Comorbid psychiatric conditions may serve as markers for impaired functioning and well-being in persons with HIV. Inclusion of sufficient numbers of appropriately trained mental health professionals to identify and treat such conditions may reduce unnecessary utilization of other health services and improve health-related quality of life in persons with HIV infection.