The relationship of response and plasma desipramine concentrations was examined in elderly depressed patients to determine whether they were more sensitive to the antidepressant effects of the drug and whether they would respond at lower plasma concentrations than younger patients. Twenty-five inpatients over the age of 60, who met criteria for major depression with melancholia, were unipolar, were not delusional, were without active medical illness or definite brain disease, and were still depressed after 1 week of hospitalization off psychotropic drugs, were treated with desipramine (2.5 mg/kg) for 3 weeks. Of the 18 patients completing the drug trial, six responded and 12 did not. Desipramine levels of responders (median, 126 ng/ml) were higher than those of nonresponders (median, 81 ng/ml; Mann-Whitney test, p less than 0.05). The threshold for response was the same as the threshold (115 ng/ml) observed in 31 nondelusional melancholic patients under the age of 60 treated in a similar manner with desipramine. Among elderly patients with levels above 115 ng/ml, four of five responded, and below this level, two of 13 responded (Fisher's exact test, p less than 0.025). Five patients not responding to the initial 3-week trial responded when desipramine was increased and the plasma level rose above 115 ng/ml. The data indicate that elderly melancholic patients to not respond to lower desipramine plasma concentrations and that therapeutic levels are similar to those for younger melancholic patients. The doses of desipramine needed to reach these levels were also similar to those required in younger patients.