BACKGROUND The effectiveness of monoamine oxidase inhibitors (MAOIs) in tricyclic resistant depression has received surprisingly little systematic study. METHODS Patients who failed to respond to sustained, adequate treatment with the tricyclic imipramine (mean maximum dosage = 260 mg/day) and interpersonal psychotherapy were withdrawn from imipramine and treated in a standardized, but open-label 6-week trial with either phenelzine (N = 4; 60 mg/day) or tranylcypromine (N = 36; mean = 38.5 mg/day) and continued interpersonal psychotherapy. RESULTS Forty of 42 patients (95%) completed the trial, of whom 23 (58%) responded to treatment. Highly significant improvement was documented on measures of depression, reversed neurovegetative symptoms, and somatic symptoms. Response was significantly correlated with severity of depression (pre-MAOI score on the Hamilton Rating Scale for Depression), severity of a composite score of anergic and reversed neurovegetative features, and low levels of improvement during initial imipramine/interpersonal psychotherapy. Of patients who met criteria for proposed subforms of anergic or atypical depression, 67% (18/27) responded (p less than .05); 77% (17/22) of patients who scored above the mean on the composite measure of anergic and reversed neurovegetative features responded (p less than .01). CONCLUSIONS These findings provide strong evidence of the utility of MAOIs in tricyclic-resistant depression, especially in patients with features such as fatigue, volitional inhibition, motoric retardation, hypersomnia, and/or weight gain.