The effect of corticotropin-releasing hormone (CRH), independent of adrenocorticotropin hormone (ACTH), was evaluated in nine healthy individuals. Cortisol release and corresponding ACTH production were determined after separate intravenous administration of ovine-CRH (1 μg/kg BW) and insulin inducing hypoglycemia (0.1 u/kg BW). Adrenocorticotropin hormone (1–24; 250 μg intravenous bolus) revealed an adequate adrenal reserve capacity in all subjects. At the time of peak cortisol response following CRH and insulin administration, IR-cortisol increments were 14 ± 1 μg/dl and 9 ± 1 μg/dl (mean ± SE), respectively (p < .05); whereas ACTH (IR-ACTH) increments were 40 ± 10 ng/1 and 53 ± 14 ng/1, respectively. The cortisol increment/ACTH increment ratios were 0.53 ± 0.09 and 0/36 ± 0.09, respectively (p < 0.05), suggesting an ACTH-independent effect of CRH on cortisol production. The authors speculate that CRH may have a direct effect on the human adrenal gland or it may release ACTH-like factors that stimulate the human adrenal cortex.