Pharmacological inhibition of excitatory neurotransmission attenuates cell death in models of global ischemia/reperfusion and hypoglycemia. The current investigations extend these observations to a model of focal ischemia. Kynurenic acid, a broad-spectrum antagonist at excitatory amino acid receptors, was used as treatment (300 mg/kg; 3 doses at 4-hour intervals) before and after focal cerebral ischemia in rats (n = 54). Preischemia but not 1 hour postischemia treatment with kynurenate attenuated infarction size (p less than 0.001) and improved neurological outcome (p less than 0.001) studied at 24 hours after injury. These data support the role of excitatory neurotransmission in acute neuronal injury and support pharmacological inhibition of cell excitation as a potential therapy for stroke.