Data on a twice-daily dosage schedule with moclobemide in the treatment of depression is limited. In this study, moclobemide 150 mg twice daily (b.i.d.) was compared to two different three-times-daily (t.i.d.) regimens with total daily dosages of 300 and 450 mg, respectively, over a 6-week period. The study was randomized, double-blind, and conducted at three university centers. Efficacy was measured on the Hamilton Depression and Anxiety Rating Scales, on the Zung Scale, and on clinical global impression. Tolerability and safety were assessed through adverse events and vital signs and on clinical global impression. One hundred seventy-eight depressed outpatients were included, and 158 completed the study. The treatment groups were comparable at baseline. No clear differences between the treatment groups could be shown with respect to efficacy. There was, however, a slightly larger decrease in the total HAM-A score in the groups receiving 150 mg b.i.d. and t.i.d. than in the third group. There were no marked differences between the groups with respect to tolerability and safety. Tolerability was rated “good” or “excellent” in 94% of patients, and there was no appreciable change in vital signs in any of the treatment groups. Moclobemide 150 mg b.i.d. is the optimal initial schedule for treatment of depression.