Several studies suggest that the hypothalamo-pituitary-adrenal (HPA) axis is exceedingly active in obeseindividuals. Experimental studies show that circulating free fatty acids (FFAs) promote the secretory activity of the HPA axis and human obesity is associated with high circulating FFAs. We hypothesized that HPA axis activity is enhanced and that lowering of circulating FFAs by Acipimox would reduce spontaneous secretion of the HPA hormonal ensemble in obese humans. To evaluate these hypotheses, diurnal ACTH and cortisol secretion was studied in 11 obese and 9 lean premenopausal women (BMI: obese 33.5 ± 0.9 vs. lean 21.2 ± 0.6 kg/m², P <0.001) in the early follicular stage of their menstrual cycle. Obese women were randomly assigned to treatment with either Acipimox (inhibitor of lipolysis, 250 mg orally four times daily) or placebo in a double blind cross-over design, starting one day prior to admission until the end of the blood-sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of plasma ACTH and cortisol concentrations. ACTH and cortisol secretion rates were estimated by multiparameter deconvolution analysis. Daily ACTH secretion was substantially higher in obese than in lean women (7950 ± 1212 vs. 2808 ± 329 ng/24h, P = 0.002), whereas cortisol was not altered (obese 36 362 ± 5639 vs. lean 37 187 ± 4239 nmol/24h, P=0.912). Acipimox significantly reduced ACTH secretion in the obese subjects (Acipimox 5850 ± 769 ng/24h, P = 0.039 vs. placebo), while cortisol release did not change (Acipimox 33 542 ± 3436 nmol/24h, P=0.484 vs. placebo). In conclusion, spontaneous ACTH secretion is enhanced in obese premenopausal women, whereas cortisol production is normal. Reduction of circulating FFA concentrations by Acipimox blunts ACTH release in obese women, which suggests that FFA's are involved in the pathophysiology of this neuroendocrine anomaly.