OBJECTIVE: The authors report on results of systematic clinical assessment of psychopathology among HIV-positive and HIV-negative intravenous drug users. METHOD: As part of a multidisciplinary baseline assessment, 147 male (85 HIV-positive and 62 HIV-negative) and 76 female (39 HIV-positive and 37 HIV-negative) intravenous drug users were evaluated with the Structural Clinical Interview for DSM-III-R and measures of psychiatric symptom severity, global functioning, and stress. RESULTS: Prevalence of a diagnosis of current depression (26%) and severity of depressive and anxiety symptoms in both HIV-positive and HIV-negative subjects were greater than in the general community, but not greater than in other studies of intravenous drug users. HIV- positive men had a higher prevalence of depressive disorders than HIV- negative men (33% and 16%, respectively), although this pattern was not found among women (26% and 30%). Diagnosis of depressive disorders and severity of depressive and anxiety symptoms were associated with a symptom-based measure of HIV illness stage, but not with indices of immune functioning (CD4+ cell count and CD4+ cell percent). CONCLUSIONS: Despite selective associations between HIV illness variables and depression, high rates of depression across HIV status in this cohort suggest that intravenous drug use and associated factors are more salient than HIV illness factors in understanding psychopathology in this population.