We investigated dextromethorphan, both a dextrorotatory opioid derivative and a clinically tested N-methyl-D-aspartate (NMDA) receptor antagonist, in a rabbit model of transient focal cerebral ischemia. Fourteen rabbits were randomly assigned to treatment with a 20 mg/kg i.v. loading dose followed by a 10 mg/kg/hr infusion of 0.4% dextromethorphan in normal saline or with an equivalent volume of normal saline alone. One hour after treatment, the rabbits underwent a 1-hour occlusion of the left internal carotid and anterior cerebral arteries followed by 4 hours of reperfusion. The seven dextromethorphan-treated rabbits showed a significant decrease in the area of neocortical severe ischemic neuronal damage (10.5%) compared with the seven normal saline-treated controls (49.6%, p less than 0.001). The dextromethorphan-treated rabbits also demonstrated significantly smaller areas of cortical edema (10.2%) on magnetic resonance imaging than the controls (38.6%, p less than 0.01). Analysis of somatosensory evoked potentials revealed recovery of the ipsilateral amplitude to contralateral values within 5 minutes of reperfusion in the dextromethorphan-treated rabbits but not in the controls (p less than 0.01). In our rabbit model of transient focal cerebral ischemia, dextromethorphan appears to protect the brain against ischemic neuronal damage and edema, as well as to promote neurophysiologic recovery. This clinically available drug should be further investigated as having potential therapeutic value in the treatment of stroke.