We have examined the effects of two monoamine oxidase (MAO) inhibitors with different mechanisms of action—phenelzine and brofaromine—on peripheral serotonergic (5-hydroxytryptamine [5-HT]) measures, sensitive to the inhibition of MAO-A (intra- and extracellular 5-HT and related metabolites in blood). Both drugs increased the concentration of 5-HT in platelet-free plasma (254%, p < 0.001) in patients with depressive illness (DSM-III-R) after 6 weeks of daily treatment. Platelet 5-HT was also increased significantly in both drug treatment groups but more marked in the patient group treated with phenelzine. The acid/amine ratio at 6 weeks was 30% of pretreat-ment values (p < 0.000) and individual variability correlated significantly with the Hamilton Rating Scale for Depression. Plasma 5-HT increased more markedly in responders than in nonresponders and a significant inverse relationship surfaced between plasma 5-HT and the Hamilton Rating Scale for Depression. The results support other reports of comparable antidepressant efficacy for brofaromine and phenelzine, both inhibitors of MAO-A in humans. The consistent relationship we found between the biochemical and clinical changes again suggests and supports a key role of 5-HT in the antidepressant effect of these MAO inhibitors.