Depressive disorders are common among 20% to 32% of people with HIV disease but are frequently unrecognized. Major depression is a recurring and disabling illness that typically responds to medications, cognitive psychotherapy, education, and social support. A large percentage of the emotional distress and major depression associated with HIV disease results from immunosuppression, treatment, and neuropsychiatric aspects of the disease. People with a history of intravenous drug use also have increased rates of depressive disorders. Untreated depression along with other comorbid conditions may increase costly clinic visits, hospitalizations, substance abuse, and risky behaviors and may reduce adherence to treatment and quality of life. HIV clinicians need not have psychiatric expertise to play a major role in depression. Screening tools improve case finding and encourage early treatment. Effective treatments can reduce major depression in 80% to 90% of patients. Clinicians who mistake depressive signs and symptoms for those of HIV disease make a common error that increases morbidity and mortality.