Nomifensine, a tetrahydroisoquinoline antidepressant, was compared with imipramine in a 4-week multicenter double-blind study of depressed outpatients (100 on nomifensine, 56 on imipramine). Nomifensine was at least as effective as imipramine in reducing depressive symptoms at average doses of 150 mg/day. When significant differences did occur on Hamilton Depression Rating Scale scores, they favored nomifensine for improvement in cognitive symptoms and interest in work and activities. Early in treatment, nomifensine patients also showed a better relationship between clinical response and side effects. The proportions of patients experiencing at least one side effect or dropping out due to side effects were almost twice as high in the imipramine group. Dry mouth and sedating effects were 2-3 times more frequent among imipramine patients. Thus, nomifensine demonstrated clinical efficacy at least comparable with imipramine but with indications of a more favorable side effects profile.