In a 6-week double-blind trial 129 outpatients with major depressive disorder received either alprazolam, imipramine or placebo. Dosage was adjustable from 0.5 mg alprazolam, 25 mg imipramine or two capsules placebo b.i.d. to 4.5 mg alprazolam, 225 mg imipramine or three capsules placebo t.i.d. Both active drugs were more effective than placebo according to all the rating scales used. Alprazolam and imipramine did not differ consistently except in the somatic symptom cluster on the Hamilton Anxiety Rating Scale. Mean final daily dosage was 2.7 mg alprazolam, 117.3 mg imipramine and 7.2 capsules placebo. Patients on alprazolam reported fewer side effects than patients on imipramine and approximately the same number as patients on placebo. Anticholinergic side effects were commonly associated with imipramine; drowsiness was the most frequent side effect with alprazolam.