This study compared the sexual functioning effects as well as the safety and efficacy of bupropion sustained release (bupropion SR) and sertraline. Three hundred sixty-four patients with normal sexual functioning and recurrent major depression were treated with bupropion SR (150-400 mg/day), sertraline (50-200 mg/day), or placebo for 8 weeks in this randomized, double-blind, multicenter study. Patients' depression, sexual functioning, and overall safety were assessed at regular clinic visits. Significantly (P < 0.05) more patients treated with sertraline experienced orgasm dysfunction compared with patients treated with bupropion SR or placebo. Bupropion SR, but not sertraline, was statistically significantly superior to placebo in improving scores on all depression scales by the end of the study. Headache occurred with similar frequency in all groups. Gastrointestinal disturbances occurred more frequently with sertraline; insomnia and agitation occurred more frequently with bupropion SR. Small decreases in mean weight were seen with both active treatments; the placebo group experienced a minor increase in mean weight. Both bupropion SR and sertraline were generally well tolerated, although sertraline was more often associated with sexual dysfunction. Bupropion SR, but not sertraline, was statistically superior to placebo in relieving depression by the end of the study. Bupropion SR may offer advantages over sertraline in treating depressed patients concerned with sexual functioning.