Prompted by a recent study suggesting that the combination of desipramine hydrochloride and fluoxetine down-regulates beta-adrenergic receptors more rapidly than either drug alone, we administered both desipramine and fluoxetine to 14 inpatients with major depression in an open, 4-week trial. Desipramine plasma levels drawn 24 hours after an initial standardized dose were used to rapidly adjust desipramine dosage and compensate for the interactive effects of fluoxetine on desipramine levels in the blood. Responses were retrospectively compared with those of 52 inpatients who were descriptively similar and previously treated in the same setting with desipramine alone. Response was significantly more rapid in the group that received both drugs. One week after treatment began, the mean change in Hamilton Depression Rating Scale scores was 42% in the group that received both drugs and 20% in the group that received desipramine alone (Mann-Whitney U test, P = .007). Two weeks after administration of the drugs, the mean change in scores of the group that received both drugs was 60%, while a 30% change was noted in the patients treated with desipramine alone (P = .001). Ten (71%) of the 14 patients in the group that received both drugs completely remitted (change in Hamilton Depression Rating Scale score of greater than 75%, and final score of less than 7) within 4 weeks, while few patients treated with desipramine alone met these criteria within 4 weeks. This preliminary study suggests that treatment with both desipramine and fluoxetine is a rapid and effective strategy for treatment of major depression, and supports recent hypotheses of noradrenergic-serotonergic synergism.