We have studied a new high-affinity competitive N-methyl-D-aspartate antagonist, D-CPP-ene (SDZ-EAA 494), in two models of focal cerebral ischemia. In the cat middle cerebral artery occlusion model (6 hours' survival), pretreatment with D-CPP-ene reduced infarct size by 64% (15 mg/kg dose) and 60% (4.5 mg/kg dose). There was no reduction in infarct size at a dose of 1.5 mg/kg. Treatment 1 hour after the occlusion reduced infarct size slightly, but not significantly. In a new model of subdural hematoma in the rat, the zone of cortical ischemic damage beneath the blood clot was reduced by 54% with D-CPP-ene pretreatment. Neuroprotective efficacy in a gyrencephalic species comparable to that of noncompetitive antagonists thus can be achieved with this agent. These experiments also indicate that competitive N-methyl-D-aspartate antagonists may be clinically useful after traumatic intracranial hematomas.