Multiple reports document hypothalamic-pituitary-axis (HPA) hyperactivity in depressed patients. Measurement of cortisol levels after ingestion of fenfluramine, a specific serotonin releaser/uptake inhibitor agent, provides an index of HPA activity. To our knowledge, this is the first study of the effect of a number of previous depressive episodes on cortisol responses to fenfluramine administration. Thirty-one unipolar depressed patients and 23 healthy volunteers entered the study. Demographic and clinical parameters were assessed and recorded. Response to fenfluramine administration was measured by the difference between maximum hourly plasma cortisol measurements after fenfluramine administration and baseline levels measured before fenfluramine administration. The number of previous major depressive episodes was a predictor of cortisol response to fenfluramine administration in depressed subjects. Higher cortisol responses were associated with more prior episodes of major depression. The relationship of cortisol to the number of previous depressive episodes remained significant after controlling for age. Our finding highlights the importance of possible cumulative effects of repeated episodes of major depression. Prevention and early recognition of depressive episodes may prevent these cumulative adverse effects.