Alterations in the activity of the hypothalamic-pituitary-adrenal (HPA) axis have been associated with obesity in humans and animals. To explore possible mechanisms responsible for the higher prevalence of obesity and its associated comorbid conditions in the black population, we studied the HPA axis of 18 black and 30 white weight- and age-matched nonobese and obese women. Waist to hip ratio, 24-h urinary free cortisol excretion, plasma cortisol responses to dexamethasone, and plasma ACTH and cortisol responses to 1 micrograms/kg ovine CRH were determined. There were no racial differences in waist to hip ratio, 24-h urinary free cortisol excretion, dexamethasone suppressibility of plasma cortisol, baseline plasma cortisol and ACTH concentrations, or plasma cortisol response to CRH. However, CRH-stimulated plasma ACTH concentrations, measured in an extraction polyclonal RIA, were significantly greater in blacks than in whites at all time points, beginning 5 min after the administration of CRH [area under the curve (AUC), 2463 +/- 288 pmol/L.min in blacks vs. 1185 +/- 78 in whites; P < 0.001]. These differences persisted when ACTH was measured by a 2-site direct immunoradiometric assay measuring the intact ACTH-(1-39) molecule (AUC, 1292 +/- 177 pmol/L.min in blacks vs. 504 +/- 95 in whites; P < 0.002). There was no significant correlation between body mass index and either cortisol or ACTH AUCs for either race, with blacks showing persistently elevated AUC for ACTH compared to whites, regardless of weight. We conclude that there are differences in the HPA axis of black and white women. How these differences may relate to the increased prevalence of obesity in the black population remains to be determined.