The phenylpiperidine derivative paroxetine is a selective serotonin reuptake inhibitor. In a double-blind 6-week trial, paroxetine was compared with amitriptyline in hospitalized patients suffering from major depression (DSM-III). One hundred fifty-three patients were enrolled in the study in seven centers in Austria and Germany. Results showed similar efficacy of both drugs after 6 weeks. The differences between groups in Mont-gomery-Asberg Depression Rating Scale and Clinical Global Impression ratings did not reach statistical significance at any time. Side effects were distributed similarly but with a significantly higher incidence of anticholinergic effects in patients treated with amitriptyline (p < 0.001), whereas agitation and insomnia were registered more often in the paroxetine group. This study supports the antidepressive efficacy of paroxetine in a sample of severely depressed inpatients.