SummaryThis pilot study examined the effectiveness of fluoxetine in depressed human immunodeficiency virus (HIV)-seropositive asymptomatic patients. Eight patients, participating in an AZT trial who met criteria for major depression syndrome (DSM-III-R), were treated with fluoxetine (20 or 40 mg/day) for 4 weeks. Initially, mean Hamilton Depression scores were 23.8 (range of 17–31), and improved to 6.4 (range of 3–10). All subjects maintained their remission over a 2-month follow-up. Fluoxetine treatment may be effective in treating major depression in HIV-seropositive asymptomatic patients.