Eleven goats (mean weight, 69 ± 16 kg) underwent 5 hrs of normothermic nonpulsatile cardiopulmonary bypass (CPB) using as priming fluid either a Ringer's based crystalloid priming solution (CP, n = 5) or a hyperosmolar oxyreplete hemosubstitute (HS, n = 6). The HS contained 20% w/v of perfluorocarbon (perfluorodecalin), its osmolarity was 800-900 mOsm/1, and the administered dose of perfluorocarbon was 30-50 ml/kg. Otherwise, the experimental procedure was identical for both groups. PaCO2 was maintained above 35 mmHg and blood flow rate at 65 ml/min/kg. Brain tissue pH, PO2, and PCO2, cerebral blood flow (CBF), arterial and venous blood gases, and other systemic variables were monitored. During CPB, P(v)O2 and brain tissue PO2 were increased significantly in the HS group. The CBF per kilogram of weight also was significantly higher in the HS group. Metabolic acidosis developed in both groups and, surprisingly, brain tissue pH and pH(v) were lower in the HS group. The mean values of P(v)CO2 and brain tissue PCO2 indicate that brain tissue hypercapnia also occurred in both groups. The HS provided long- term stability and compatibility with electrolytes, and did not cause major complications or allergic reactions during CPB. Perfluorocarbon based HSs improve tissue oxygenation, eliminate the risk of infection due to homologous transfusions, do not require blood type matching, have a shelf life longer than that of blood, and, therefore, they can be an important factor in diminishing the incidence of complications after CPB.