The effects of opiate receptor antagonism on the fetal cardiovascular response to hypoxemia were examined by means of the radionuclide-labeled microsphere technique. Heart rate, blood pressure, and cardiac output were measured during baseline periods, during hypoxemia, and before and after infusion of either naloxone (1 mg/kg) or an equivalent volume of 0.0% saline solution. Seventeen fetal sheep were subjected to maternal hypoxemia by allowing the ewes to breathe 10% oxygen (3% carbon dioxide, 87% nitrogen). The fetuses responded with bradycardia (p less than 0.002 compared with control), increased blood pressure (p less than 0.002 compared with control), and no significant change in combined ventricular output or placental blood flow. After naloxone, the bradycardia increased by 10% (p less than 0.001), and both combined ventricular output and placental blood flow fell by 20% (p less than 0.01 and p less than 0.01, respectively). The fetal bradycardic response to naloxone was reversible with atropine. In fetuses with normal oxygenation of the blood (normoxemic), naloxone had no significant effect on heart rate and blood pressure. These data indicate that endogenous opiates (e.g., endorphin and enkephalin) are important in regulating the fetal circulation during hypoxia, and that the effects of opiate receptor antagonism may be mediated through the autonomic nervous system.