OBJECTIVE To ascertain whether depressive symptoms as determined by the Center for Epidemiologic Studies-Depression scale (CES-D) predict accelerated mortality and worse medical outcomes in patients infected with human immunodeficiency virus (HIV). METHODS Eight-year cohort study with semiannual follow-up. METHODS Community volunteers. METHODS A total of 1809 HIV-seropositive homosexual men without the acquired immunodeficiency syndrome (AIDS) who entered the Multicenter AIDS Cohort Study in 1984 or 1985. Eight-year follow-up data were available on 75% of eligible participants. METHODS Times to AIDS, death, and prophylactic treatment, and slopes describing the decline in CD4 count for each individual participant. RESULTS Using a conventional definition of depression (CES-D > or = 16 at the first study visit), 21.3% of participants were classified as depressed. Depressed participants had lower CD4 counts and reported more AIDS-related symptoms. There were no significant differences between depressed and nondepressed participants on any of the outcome measures (P > .05 in all cases). In contrast, men reporting AIDS-related symptoms had shorter times to AIDS and to death even after adjusting for CD4 counts (P < .01). The analyses were repeated, with similar results, using different definitions of depression based on the CES-D. CONCLUSIONS We find no evidence that depressive symptoms independently prognosticate worse outcomes in HIV infection. Because of associations of depression with symptom reports, CD4 counts, and indicators of socioeconomic status, future studies of the relationship between depression and HIV outcome should consider these variables as confounders.