Objectives Cerebral ischemia can occur during cardiopulmonary bypass, especially during low flow. HBOC-201 (OPK Biotech, Cambridge, Mass) is a hemoglobin-based oxygen-carrying solution that enhances oxygen delivery. This project evaluated the benefits on total body and cerebral oxygen delivery and consumption using HBOC-201 during cardiopulmonary bypass. Methods Twelve immature swine were assigned to one of 2 groups. One group used HBOC-201 in pump prime, and the other used donor porcine blood. Cardiopulmonary bypass was initiated and then flow was serially decreased from 100% to 75%, to 50%, and then back to full flow. At each interval, 15O positron emission tomographic analysis was performed, and blood was collected. Total body and cerebral oxygen delivery and consumption were calculated. Statistical analysis was performed with a Tukey–Kramer adjusted P value based on a repeated measures linear model on log-transformed data. Results Total and plasma hemoglobin levels were higher in the HBOC-201 group. Oxygen delivery and consumption were not statistically different but did tend to be higher in the HBOC-201 group. Mixed venous saturation was lower in the HBOC-201 group but not significant. Mild metabolic acidosis with increased lactate levels developed in the blood group. Mean cerebral blood flow decreased in both groups when total flow was 50%. In the HBOC-201 group cerebral oxygen metabolism was maintained. Conclusions The addition of HBOC-201 for cardiopulmonary bypass appears to improve oxygen use and minimize anaerobic metabolism. Cerebral oxygen use was preserved in the HBOC-201 group, even during decrease in blood flow. These findings support the reported improved oxygen-unloading properties of HBOC-201 and might provide a benefit during cardiopulmonary bypass.