In a double-blind multi-centre study of general practice patients with DSM-III-R major depressive disorder, sertraline (50 or 100 mg/day) was compared with dothiepin (75 or 150 mg/day) and with placebo. There were 83, 96 and 90 patients evaluated in the respective treatment groups; treatment lasted 6 weeks. Patients were assessed on the MADRS, CGI, and Leeds Self-rating Scales. Statistically significant differences (p < 0.05) between sertraline and placebo were found on MADRS and CGI but not the Leeds Scales. In the mild subgroup analyses, there were no significant differences between sertraline and placebo. However, clear significant differences (p < 0.05) between sertraline and placebo were present in the severe subgroup. Dothiepin failed to achieve a statistically significant difference from placebo on any analyses. Seventy-six per cent of patients were treated with 50 mg sertraline and 81% of patients received 150 mg dothiepin. Both sertraline and dothiepin were generally well tolerated; the most frequent side effects with sertraline were nausea, dizziness and headache; with dothiepin the most frequent side effects were dry mouth, somnolence and headache.