Abstract To explore the interrelationships between the serotoninergic system and the hypothalamic-pituitary-adrenal (HPA) axis in human obesity, we evaluated cortisol and adrenocorticotropic hormone (ACTH) response to synthetic human corticotropin-releasing hormone (hCRH, 1 μg/kg intravenously [IV]) before and after stimulation of the serotoninergic system by dextrofenfluramine (d-FF, 30 mg/d for 3 months) in nine obese women. These responses were compared with a CRH test (1 μg/kg) carried out in nine age-matched normal-weight women. Plasma cortisol of obese subjects did not significantly increase after CRH (peak value 127.1 ± 11.2 ng/mL v 104.1 ± 9.5 ng/mL). This response was lower ( P < .005) than in the controls, in whom the basal cortisol value of 120.6 ± 11.8 ng/mL reached a peak value of 221.2 ± 13.4 ng/mL. However, after administration of d-FF, CRH significantly increased ( P < .0001) plasma cortisol (peak value 170.6 ± 18.0 ng/mL v 111.5 ± 10.8 ng/mL) and the response was enhanced ( P < .05) as compared with that obtained before d-FF. The ACTH levels of our patients showed a small increment after CRH injection (peak value 13.5 ± 1.7 pg/mL v 9.6 ± 1.1 pg/mL), but the hormonal response was lower ( P < .005) than in controls (peak value 38.1 ± 5.5 pg/mL v 13.8 ± 0.8 pg/mL). However, after d-FF, CRH induced a significant increment ( P < .05) in plasma ACTH at 30 minutes (20.4 ± 3.7 pg/mL v 10.9 ± 0.9 pg/mL) and 45 minutes (18.0 ± 2.6 pg/mL), even though this response was not significantly different from that observed before d-FF administration. In conclusion, we found a blunted pituitary response to CRH in obese subjects, which was improved by serotoninergic stimulation. This finding indicates a reduced serotonin activity in these subjects and shows that the serotoninergic system is also involved in the regulation of the HPA axis function.