Bupropion and trazodone were compared in a two-center, double-blind clinical trial of outpatients with moderate to severe major depression. After a 1-week placebo lead-in, 124 patients were randomly assigned to receive either bupropion (N = 63) or trazodone (N = 61) for 6 weeks; data from 111 patients were used in the efficacy analysis. Dosing ranged from 225 to 450 mg/day for bupropion and 150 to 400 mg/day for trazodone. The overall efficacy for each of the two drugs was similar; although improvement in the trazodone treatment group was significantly greater on day 7 because of the effects on sleep. At the end of treatment, 58% of the bupropion-treated patients and 46% of the trazodone-treated patients were considered much or very much improved. Weight measurements at the time of discontinuation indicated a 2.5-lb mean weight loss for the bupropion treatment group and a 1.2-lb mean weight gain for the trazodone treatment group. The adverse experience profiles for bupropion and trazodone were consistent with their known pharmacologic profiles (i.e., activating versus sedating). Anorexia and anxiety were reported significantly more often for the bupropion treatment group, whereas somnolence, appetite increase, and edema were reported significantly more often for the trazodone treatment group.