In order to evaluate serotonergic function in obsessive-compulsive disorder (OCD), plasma cortisol response to d-fenfluramine (30 mg p.o.) was examined in 20 drug-free obsessive-compulsive patients (10 males and 10 females) and in 20 age- and sex-matched healthy subjects, under double-blind, placebo-controlled conditions. We found that: (a) baseline plasma cortisol secretion was significantly increased in patients with OCD; (b) in healthy subjects, the cortisol response to d-fenfluramine was evident in women, but no in men; (c) plasma cortisol response to the serotonergic challenge did not differ between patients and controls, but it was significantly reduced in female patients as compared to healthy women. These results demonstrate a hyperactivity of the hypothalamo-pituitary-adrenal axis in obsessive-compulsive patients and suggest a dysfunction of 5-HT transmission in female patients.