Using awake, chronically catheterized newborn pigs, we measured cerebral blood flow (CBF), net cerebral vascular 6-keto-prostaglandin F1αproduction, and cerebral metabolic rate of oxygen (CMRO2) during hypercapnia and during hypercapnia at increased mean airway pressure (Pāw), both before and after treatment with indomethacin. CBF nearly doubled during hypercapnia. The hypercapnia-induced cerebral hyperemia was maintained when Pāw was increased from 3 ± 2 to 16 ± 4 cm H2O during hypercapnia. Sagittal sinus pressure increased in proportion to the increase in Pāw, and cardiac output was unchanged. Net cerebral production of 6-keto-prostaglandin F1αincreased from 9 ± 1 to 15 ± 1 ng/min/100 g tissue during hypercapnia and increased dramatically to 57 ± 1 ng/min/100 g when hypercapnia was coupled with an increase in Pāw. CMRO2was not changed by either hypercapnia or increased Pāw. After indomethacin, CBF decreased and cerebral vasodilation to hypercapnia did not occur. After indomethacin, adding increased Pāw during hypercapnia dropped CBF below baseline, adversely affecting CMRO2. These results suggest that cerebral hypercapnic hyperemia requires brain prostanoid production and that when Pāw is increased during hypercapnia, the contribution of prostanoids to maintaining CBF is increased. Increasing ventilation pressure during hypercapnia in piglets pretreated with indomethacin compromises CBF sufficiently to reduce CMRO2.