Pharmacologic inhibition of excitatory amino acid neurotransmission improves physiologic, metabolic, and neurobehavioral outcome following experimental brain trauma. However, no studies to date have demonstrated pharmacologically-induced attenuation of histopathological changes associated with experimental brain injury models. The present study examined the effects of kynurenate, an NMDA and non-NMDA receptor antagonist, on neuronal survival in the hippocampus after lateral fluid-percussion brain injury in the rat. Animals (n = 10/treatment) randomly received an intravenous injection of either kynurenate (300 mg/kg) or buffer (equal volume) 15 min following fluid-percussion brain injury of moderate severity. Two weeks after injury, animals were sacrificed and neuronal cell loss in the hippocampus was examined with Nissl staining. Selective loss of neurons in the CA3 region of the hippocampus, which has previously been characterized in this model of brain injury, was found to be significantly attenuated following kynurenate treatment (P < 0.05). These data suggest that pharmacologic compounds which are known to have beneficial effects on neurobehavioral and physiological outcome following brain injury may also significantly attenuate post-traumatic neuronal cell loss. Our results also support other recent data that pharmacological intervention with an excitatory amino acid receptor antagonist may be of therapeutic value in the treatment of brain injury.