Objective: The effect of inhibiting prostag;andin synthesis on the fetal metabolic response to hypoxemia was examined by infusing indomethacin during periods of reduced maternal uterine blood flow. Study design: In seven fetal sheep we administered a 6-hour infusion of either indomethacin (n = 5), indomethacin plus prostaglandin E2, or vehicle solution (n = 5). The last 4 hours of each infusion period coincided with a period of fetal hypoxemia induced by reduced maternal uterine blood flow. Results: During reduced maternal uterine blood flow indomethacin infusions caused a significantly greater reduction in pHA (reduced from 7.36 ± 0.01 to 7.10 ± 0.02) than both the vehicle (from 7.36 ± 0.01 to 7.20 ± 0.03) and indomethacin plus prostaglandin E2 infusions (from 7.36 ± 0.01 to 7.18 ± 0.02). Before reduced maternal uterine blood flow was induced, indomethacin significantly elevated fetal plasma glucose and lactate concentrations from 0.6 ± 0.04 and 2.2 ± 0.1 to 1.3 ± 0.2 and 6.7 ± 0.7 mmol/L, respectively. During reduced maternal uterine blood flow indomethacin caused a significantly greater increase in plasma glucose and lactate concentrations than the vehicle; plasma glucose and lactate concentrations increased to a maximum of 1.8 ± 0.2 and 22.7 ± 0.8 mmol/L, respectively, during indomethacin infusions compared with 1.1 ± 0.1 and 15.7 ± 1.7 mmol/L, respectively, during vehicle infusions. The addition of prostaglandin E2 to the indomethacin infusion prevented the enhanced increase in glucose and lactate concentrations during reduced maternal uterine blood flow and caused a significant increase in fetal plasma insulin concentrations from 12.6 ± 0.7 to 60.9 ± 28.1 μU/ml. Conclusion: The inhibition of prostaglandin synthesis during fetal hypoxemia alters the metabolic response of the fetus, leading to a severe metabolic acidosis.