N-methyl-D-aspartate (NMDA) receptor antagonists have been found to be protective after cerebral ischemia. However most of these drugs have limited value as neuroprotectives in clinical therapy because of their side effects. Memantine is a noncompetitive NMDA receptor antagonist and it has been used for the treatment of various cerebral disorders with relatively few side effects. We investigated the beneficial effects of Memantine and compared its effect with MK-801 in a temporary focal cerebral ischemia model. As cerebral ischemia model three hours middle cerebral artery occlusion (MCAO) with intraluminal thread and three hours reperfusion was used. 78 male Spraque-Dawley rats were divided into three groups as follows: Control (Saline), treatment 1 (MK-801), and treatment 2 (Memantine) groups. In the treated groups, 15 minutes after MCAO, MK-801 and Memantine were administered in amounts of 1 mg/kg and 10 mg/kg intraperitoneally respectively. After a 3 hour period of reperfusion, the animals were examined for neurological deficits and then killed. The following values were measured; cerebral water content, blood brain barrier (BBB) permeability at the core and periphery of the ischemic hemisphere and contralateral hemisphere and infarct volumes. The severity of neurological deficit (p < 0.001) and infarct volume (p < 0.001) was reduced in both Memantine and MK-801 treated groups compared with saline treated groups. Memantine attenuated brain edema formation and BBB permeability at the periphery (p < 0.01), MK-801 both at the core (p < 0.05) and the periphery (p < 0.01) of the ischemia. These results demonstrated that the NMDA receptor antagonists Memantine and MK-801 were neuroprotective when given 15 min after MCAO in temporary focal cerebral ischemia.