The efficacy and the safety of moclobemide (400-600 mg/day), a reversible and selective inhibitor of monoamine oxidase-A (RIMA) and of clomipramine (100-150 mg/day) were compared respectively in 98 and 93 nonmelancholic, nonpsychotic out-patients with a DSM-III major depressive episode over 6 weeks and up to 3 months, in a multi-center double-blind trial. No statistically significant difference between the treatments was found on the number of responders, at 6 weeks and 3 months, to the Hamilton Depression Rating Scale (HDRS), which was the main criterion for efficacy. The sample size was sufficient to detect a difference of approximatively 20% in response rates. Reduction of the total scores on HDRS and Covi anxiety scale was comparable for both treatments, but the reduction on the Retardation Depressive Scale (RDS) was significantly higher with moclobemide at the 1- and 2-week assessments. According to the RDS as well as the global impression of both patient and physician, a somewhat earlier onset of antidepressant action was evident in the moclobemide group. Tolerance was significantly better in the moclobemide group, mainly due to a lower frequency of weight gain, sedation and anticholinergic effects.