Objective: This study was designed to determine the role of adenosine in the hypoxic release of corticotropin in fetal sheep. Study Design: The adenosine receptor antagonist 8-phenyltheophylline or the vehicle was infused intra-arterially to chronically catheterized fetal sheep (>0.8 term) during an hour of fetal hypoxemia (Pa O₂ 14 mm Hg). Control studies were also performed in which 8-phenyltheophylline or the vehicle was administered to normoxic fetuses. Results: 8-Phenyltheophylline abolished hypoxia-induced bradycardia and hypertension and produced a nearly 5-fold greater rise in fetal plasma concentrations of corticotropin and approximately a 3-fold greater increase in plasma cortisol levels. During normoxia 8-phenyltheophylline increased plasma cortisol concentrations by 2-fold without altering corticotropin levels, mean arterial blood pressure, or heart rate. Conclusion: Adenosine blunts fetal corticotropin release during hypoxia, which in turn reduces cortisol secretion. At lower corticotropin concentrations, adenosine also appears to dampen the cortisol response through direct effects on the adrenals. (Am J Obstet Gynecol 1999;180:1272-7.)