In depression that is resistant to tricyclic antidepressant (TCA) therapy, the substitution of a selective serotonin re-uptake inhibitor (SSRI), clomipramine, or a monoamine oxidase (MAO) inhibitor has been recommended. However, adding an additional antidepressant medication from a different drug class may produce even more rapid efficacy. In this regard, the combination of a MAO inhibitor or a SSRI plus a TCA has been shown to be of value in treatment-resistant depression (TRD). In this report, we examined the efficacy of clomipramine augmentation in 20 patients who failed to respond to either a MAO inhibitor or fluoxetine therapy for at least a 6-week period, and compared this to a third group given MAO inhibitor plus a conventional TCA. Two out of 9 (22%) MAO inhibitor/clomipramine patients and 4 out of 11 (36%) fluoxetine/clomipramine patients improved (Fisher's Exact test, P = ns), compared to 3 out of 7 (43%) patients taking MAO inhibitor/TCA (P = ns). However, the MAO inhibitor/clomipramine group experienced significantly more adverse events which necessitated stopping treatment (56%) when compared to the fluoxetine/clomipramine (9%) and compared to the MAO inhibitor/TCA group (0%) (chi 2 = 8.9, df = 2, P < 0.05). These adverse events included several cases of serotonin syndrome of mild to moderate severity. These observations indicate that clomipramine augmentation of a failed MAO inhibitor trial is of marginal efficacy (compared to augmentation with a conventional TCA) and should be employed with extreme caution.