This study tested the hypothesis that CGRP has a role in mediating the in vivo fetal adrenal glucocorticoid response to acute stress. The hypothesis was tested by investigating the effects of fetal treatment with a selective CGRP antagonist on plasma ACTH and cortisol responses to acute hypoxemia in the late gestation sheep fetus. Under anesthesia, 6 fetuses at 0.8 of gestation were surgically instrumented with vascular catheters. Five days later, fetuses were subjected to 0.5 h hypoxemia during treatment with either i.v. saline or a CGRP antagonist, in randomized order, on different days. Treatment started 30min before hypoxemia and ran continuously until the end of the challenge. Arterial blood samples were collected for plasma ACTH and cortisol measurements (RIA) and blood gas monitoring. CGRP antagonism did not alter basal arterial blood gas or endocrine status. During hypoxemia, similar falls in P_aO₂ occurred in all fetuses. During saline infusion, acute hypoxemia induced significant increases in fetal ACTH and cortisol concentrations. During CGRP antagonism, the pituitary-adrenal responses were markedly attenuated. Correlation of paired plasma ACTH and cortisol values from all individual fetuses during normoxia and hypoxemia showed positive linear relationships, however neither the slope nor the intercept of the peptide-steroid relationship were affected by CGRP antagonism. These data support the hypothesis that CGRP is involved in the in vivo regulation of fetal adrenocortical steroidogenesis during acute hypoxemia. In addition, the data reveal that CGRP may have a role in the control of other components of the HPA axis during stimulated conditions in fetal life.