We studied the efficacy of systemic pre-treatment with dextrorphan (DX), a clinically tested N-methyl-D-aspartate (NMDA) antagonist, in a rabbit model of transient focal cerebral ischemia. Rabbits were treated with either a 24 mg/kg i.v. loading dose followed by 12 mg/kg/h i.v. infusion of 0.48% DX in normal saline (NS), or with an equivalent volume of NS alone. One and 1/2 h after starting the drug or NS, the rabbits underwent a 1 h occlusion of the left internal carotid and anterior cerebral arteries, followed by 4 h of reperfusion. The DX-treated rabbits had significantly less neocortical ischemic neuronal damage (7.4%) than the normal saline group (31.6%) and demonstrated a significant decrease in ischemic cortical edema. DX may prove useful in the treatment of clinical cerebrovascular disease.