Little is known about the effects of intentional weight loss on the function of the hypothalamic-pituitary-adrenal (HPA) axis of obese individuals. We studied the HPA axis of 34 healthy obese women (body mass index, 40.2 6 7.9 kg/m2) before and after a 21.0 6 7.9-kg weight loss induced by a 26-week weight loss program that included 12 weeks of a 3350 kJ/day (800 Cal/day) liquid formula diet, 6 weeks of gradual refeeding, and 6 weeks of caloric stabilization at 5020 - 6280 kJ/day (1200 -1500 Cal/day). Obese subjects were evaluated twice: before caloric restriction and during the last 3 weeks of caloric stabilization with a 3-h evening 1 mg/kg ovine CRH (oCRH) stimu- lation test. CRH-stimulated ACTH and cortisol values were compared to those of a control group of 12 normal weight women. Before caloric restriction, both ACTH and cortisol responses to oCRH were similar in obese women and normal weight controls. Weight loss did not significantly alter the ACTH response to oCRH; however, the total plasma cortisol response to oCRH decreased significantly with weight loss (area under the curve, 96,320 6 21,040 nmol/Lzmin before weight loss; 82,450 6 22,460 nmol/Lzmin after weight loss; P , 0.001). Cor- tisol-binding globulin also decreased significantly after weight loss (2,270 6 1,050 nmol/L) compared either to values obtained before weight loss (3,590 6 1,360 nmol/L; P , 0.001) or to those of normal weight controls (3,910 6 1,400 nmol/L; P , 0.001). Assay for plasma free cortisol, either before or 180 min after oCRH treatment, showed no significant changes in cortisol responses resulting from weight loss. As plasma free cortisol was not altered by weight reduction, the decrease in the total cortisol response to oCRH after weight loss appears to be secondary to significant decreases in cortisol-binding globulin. We conclude that when obese women lose large amounts of weight with a 3350 kJ/day, very low energy diet, such weight reduc- tion does not significantly affect the HPA axis. (J Clin Endocrinol Metab 82: 1874 -1878, 1997)