Background and Purpose Cerebral ischemia and stroke are leading causes of morbidity and mortality. An approach to protecting the brain during ischemia is to try to increase the delivery of oxygen via the residual blood flow through and around ischemic tissue. To test this hypothesis, we used a novel oxygen delivery agent, RSR-13 (2-[4-[[(3,5-dimethylanilino)-carbonyl]-methyl]phenoxy]-2-methylpropionic acid). Intravenous administration of RSR-13 increases oxygen delivery through allosteric modification of the hemoglobin molecule, resulting in a shift in the hemoglobin/oxygen dissociation curve in favor of oxygen delivery. Methods We studied RSR-13 in a feline model of permanent middle cerebral artery occlusion to assess its effects on cerebral oxygenation and infarct size. A randomized, blinded study of RSR-13 (n=6) versus 0.45% saline (n=12) was conducted, after an RSR-13 dose-escalation study (n=4). Drug was administered as a preocclusion bolus followed by a continuous infusion for the duration of the experiment (5 hours). Brain oxygen was measured continuously with the use of a Clark oxygen electrode. Infarct size was measured at 5 hours after occlusion with computer-assisted volumetric analysis. Results The drug treatment group had consistently higher mean brain oxygen tension than controls (33±5 and 27±6 mm Hg, respectively) and significantly smaller infarcts (21±9% versus 33±9%, respectively; P <.008). We observed an inverse relationship between the dose response of RSR-13 (the shift in the hemoglobin/oxygen dissociation curve) and infarct size. Conclusions These results are evidence that allosteric hemoglobin modification is protective to the brain after acute focal ischemia, providing a new opportunity for neuroprotection and raising the possibility of enhancing the protective effect of thrombolysis and ion channel blockade.