Objective: Selective cerebral perfusion is a proven adjunct to hypothermia for neuroprotection in complex aortic surgery. The ideal conditions for the provision of selective cerebral perfusion, however, including optimal perfusion pressure, remain unknown. We investigated the effects of various perfusion pressures during selective cerebral perfusion on cerebral physiology and outcome in a long-term porcine model. Methods: Thirty piglets (26.3 ± 1.4 kg), cooled to 20°C on cardiopulmonary bypass with α-stat pH management (mean hematocrit 23.6%), were randomly assigned to 90 minutes of selective cerebral perfusion at a pressure of 50 (group A), 70 (group B), or 90 (group C) mm Hg. With fluorescent microspheres and sagittal sinus sampling, cerebral blood flow and cerebral oxygen metabolism were assessed at baseline, after cooling, at two points during selective cerebral perfusion, and for 2 hours after cardiopulmonary bypass. Visual evoked potentials were monitored during recovery. Neurobehavioral scores were assessed blindly from standardized videotaped sessions for 7 postoperative days. Results: Cerebral blood flow during selective cerebral perfusion was significantly increased by higher-pressure perfusion (P = .04), although all groups sustained similar levels of cerebral oxygen metabolism during selective cerebral perfusion (P = .88). After the end of cardiopulmonary bypass, the cerebral oxygen metabolism increased to above baseline in all groups, with the highest levels seen in group C (P = .06). Intracranial pressure was significantly higher during selective cerebral perfusion in group C (P = .0002); visual evoked potentials did not differ among groups. Neurobehavioral scores were significantly better in group A (P = .0002). Conclusion: Selective cerebral perfusion at 50 mm Hg provides neuroprotection superior to that at higher pressures. The increased cerebral blood flow with higher-pressure selective cerebral perfusion is associated with cerebral injury, reflected by high post-cardiopulmonary bypass cerebral oxygen metabolism and poorer neurobehavioral recovery.