Glutamate neurotoxicity has been implicated in the pathophysiology of cerebral ischemia-reperfusion injury. Therefore, we investigated the effect of glutamate receptor antagonist riluzole in a rabbit model of warm cerebral ischemia-reperfusion. A total of 16 New Zealand rabbits were randomly assigned to one of three groups: Riluzole group (n = 6), which received riluzole (8 mg/kg), control group (n = 5), which received only vehicle before ischemic period, and sham group (n = 5), which had the same operation but did not undergo clamping. To induce warm cerebral ischemia the left carotid artery was occluded for 15 minutes and then reperfusion was allowed. The rabbits were killed after 4 hours of reperfusion. The brain slices were harvested for immunohistochemical examination of platelet endothelial cell adhesion molecule (PECAM) expression and blood samples were taken for measurement of serum superoxide dismutase (SOD), catalase, myeloperoxidase (MPO) and malondialdehyde (MDA) levels. The results indicated that riluzole treatment reduced the relative levels of malondialdehyde and myeloperoxidase and increased SOD levels (P < 0.001). No statistically important difference was determined between riluzole and sham group with respect to these results. We did not find any significant difference in catalase levels among three groups. Immunohistochemical examination showed significant decrease of PECAM expression in riluzole treated animals (P < 0.05). Our findings suggested that riluzole may protect brain in a setting of severe ischemia-reperfusion injury and therefore, be considered for clinical usage.