Indomethacin lowers fetal and neonatal brain blood flow and may reduce the risk of periventricular-intraventricular hemorrhage. However, concerns have been raised that cerebral O2metabolism may be compromised at lower cerebral perfusion pressures. In 17 near-term lamb fetuses, changes in brain blood flow and cerebral O2metabolism (CMRo2) were measured at mean carotid arterial pressures (MCBP) ranging from 8 to 70 mm Hg. MCBP was adjusted by inflating balloon occluders around the aortic isthmus and brachiocephalic trunk. This was done before and during intrauterine pulmonary ventilation and oxygenation. Nine fetuses were pretreated with indomethacin (1 mg/kg i.v.): eight served as controls. Changes in brain blood flow were assessed from carotid arterial blood flow (Qcar, ml/min) measured with flow transducers. In 15 animals, brain blood flow was also measured intermittently by radionuclide-labeled micro-spheres (Qbrain). Qcarcorrelated closely with Qbrain(r- 0.94,p< 0.0001); this relationship was not altered by indomethacin or by ventilation with oxygen. In the nonventilated fetuses, indomethacin decreased Qcarat pressures above the lower limit of cerebral autoregulation (43 mm Hg). However, at MCBP below 44 mm Hg, Qcarwith indomethacin was not significantly different from controls. CMRo2fell when MCBP was decreased below 30 mm Hg (range 8–29 mm Hg), but there was no significant difference between control and indomethacin-pretreated fetuses. In the ventilated fetuses, indomethacin reduced the slope of the pressure-flow relationship above the lower limit of cerebral autoregulation (43 mm Hg), suggesting improved cerebral autoregulation. When MCBP was decreased below 44 mm Hg (range 10–43 mm Hg), indomethacin did not lower Qcaror CMRo2as compared with controls. We conclude that indomethacin reduced cerebral perfusion in the nonventilated fctuses and also appeared to improve cerebral autoregulatory function in the ventilated and oxygenated fetuses, without compromising cerebral metabolism at lower cerebral perfusion pressures.