To date, the authors know of no prospective studies of sustained-release bupropion in depressed HIV-seropositive patients. The purpose of this study was to evaluate the efficacy and tolerability of sustained-release bupropion in 20 depressed HIV-positive adult outpatients. Twenty outpatients with HIV spectrum illness, a DSM-IV-diagnosed major depressive disorder confirmed with the Structured Clinical Interview for DSM-IV, and Mini-Mental State Examination scores >20 were recruited into a 6-week, open-label, flexible-dose study of sustained-release bupropion (100-300 mg/day). Twelve patients (60%) responded to sustained-release bupropion at a mean dose of 265 mg/day. Five patients (25%) discontinued study participation secondary to adverse events. Preliminary findings suggest that sustained-release bupropion is effective for the treatment of depression in HIV-positive patients, regardless of HIV clinical staging. Furthermore, it appears to be well tolerated in patients with AIDS-related medical conditions.