A substantial number of depressed patients will experience a chronic, treatment-resistant affective disorder. Aggressive treatment of these patients with various drug combinations, unconventional antidepressants, or electroconvulsive therapy has met with only partial success. There remains a pressing need to identify more effective methods of utilizing "first-line" antidepressant agents to achieve a more rapid therapeutic action. To this end, we initiated a study using high doses of the MAO inhibitor tranylcypromine, at a range of 90 mg to 170 mg daily, in seven refractory depressed patients who had failed to respond to at least three prior treatments regimens. Four out of seven subjects (57%), who had failed to respond to a mean of 8 +/- 5 prior treatment, had a complete response, and one patient had a partial response to high dose tranylcypromine. The mean SD maximum tranylcypromine dose for the responders was 112 +/- 16 mg daily (range 90 mg to 130 mg). Response did not appear to be a function of severity of illness, duration of present episode, or the number of prior treatment failures. Overall, the side effect profile was favorable, and no "cheese reactions" were encountered. These observations are of clinical significance and suggest the need for further controlled studies using high doses of tranylcypromine.