Unanesthetized newborn pigs were studied to evaluate the immediate (10 min) and delayed (45 min) effects of increased ventilation pressure coupled with cyclooxygenase inhibition. Cardiac output and cerebral blood flow were measured at a low (5 cm H2O) and high (30 cm H2O) mean airway pressure (Paw) before and 45 min after 5 mg/kg of indomethacin. In a second group, these parameters were also measured 10 min after indomethacin was given during ventilation at a Paw of 30 cm H2O. Before treatment with indomethacin, increasing Paw decreased cardiac output without affecting cerebral blood flow. Baseline (Paw = 5 cm H2O) cerebral blood flow decreased 40% 45 min after indomethacin treatment. Adding the stress of a ventilation-induced drop in cardiac output did not further depress cerebral blood flow. When indomethacin was administered during high Paw, cerebral blood flow decreased markedly within 10 min. Cerebral oxygen consumption was maintained by increasing oxygen extraction. Therefore, indomethacin decreases cerebral blood flow at a high Paw. The fall in cerebral blood flow decreases brain oxygen delivery. However, cerebral oxygen consumption is maintained by an increase in oxygen extraction.