Prevention of hyperperfusion of the brain in the perinatal period has been thought to be an important mechanism by which indomethacin reduces the risk for severe periventricular-intraventricular hemorrhage. The present study investigated whether an indomethacin-induced enhancement of the upper limit of cerebral vascular autoregulatory ability in the neonate contributed to this reduction in cerebral blood flow. In seven anesthetized newborn lambs, we measured temporal blood flow velocity (TMFV) in the carotid artery over a wide range of mean aortic blood pressures (MABP) before and 30 min after an i.v. dose of 1 mg/kg indomethacin. TMFV in the carotid artery was used as an estimate for changes in cerebral blood flow. Stepwise changes in MABP of approximately 10 mm Hg were achieved by progressive balloon occlusion of the thoracic aorta or by progressive bleeding. Multiple linear regression analysis of TMFV versus MABP, indomethacin, and the possible interactive effects confirmed that, at MABP values up to 86 mm Hg, indomethacin lowered TMFV of the carotid artery. Above 86 mm Hg, indomethacin reduced the slope of the TMFV-MABP relationship, indicating an improvement of the autoregulatory ability of the cerebral vascular bed. There was a significant interanimal variability. Thus, indomethacin may reduce the risk for PIVH by limiting cerebral blood flow, especially during increased cerebral perfusion pressures, which often occur after birth asphyxia.