Transfusion of anemic patients with hemoglobin-based oxygen carriers (HBOCs) may improve cerebral oxygen delivery. Conversely, cerebral vasoconstriction, associated with HBOC transfusion, could limit optimal cerebral tissue oxygenation. We hypothesized that hemodilution with a HBOC would maintain cerebral tissue oxygenation, despite the occurrence of cerebral vasoconstriction. Isoflurane-anesthetized rats (100% oxygen) underwent direct measurement of mean arterial blood pressure (MAP), caudate tissue oxygen tension (P(Br)o(2)), and regional cortical cerebral blood flow (rCBF) before and after 50% of the estimated blood volume (30 mL/kg) was exchanged with either an HBOC (hemoglobin raffimer; Hemolink) or pentastarch (n = 6). Hemodilution with hemoglobin raffimer caused a transient increase in P(Br)o(2) from 24.9 +/- 13.3 mm Hg to 32.2 +/- 19.1 mm Hg (P < 0.05), a sustained increase in MAP, and no change in rCBF. Arterial blood oxygen content was maintained despite an increase in methemoglobin and reduced oxygen saturation. Hemodilution with pentastarch caused a transient increase in MAP, no change in P(Br)o(2), and a sustained increase in rCBF (P < 0.05), whereas the hemoglobin concentration and oxygen content were significantly reduced. Hemodilution with hemoglobin raffimer augmented P(Br)o(2) and prevented the increase in rCBF observed after similar hemodilution with pentastarch. These data suggest that transfusion with hemoglobin raffimer may help to maintain cerebral oxygenation during severe anemia.