DSM IV defines its atypical features depression modifier mainly by current symptoms. Relative to depressed patients with melancholic features, those with atypical features often present with earlier onset of a more chronic disorder and are less likely to benefit from tricyclic antidepressant (TCA). We, therefore, hypothesized that within depressed patients with atypical features those with illness course most similar to that of melancholia would be most TCA-responsive, those whose illness course least resembled that of melancholia would be least TCA responsive. Two patient groups were treated with TCA, monoamine oxidase inhibitor, or placebo with nonresponders crossed to alternative treatment. One group met DSM IV criteria for atypical features and the other nearly met these criteria. Early onset, chronically depressed patients with DSM IV atypical features had poor TCA response relative to others. Patients with ''probable'' atypical features (mood reactivity plus one associated atypical feature) and nonresponders crossed to alternate treatment confirmed this. Findings suggest that application of DSM IV atypical features might best be limited to those with early onset of chronic dysphoria.