Evidence has accumulated to implicate the excitatory amino acid neurotransmitters, glutamate and aspartate, in the pathophysiology of central nervous system (CNS) ischemic injury. It appears from both in vivo and in vitro experiments that they exert their excitotoxic effects in CNS ischemia by their actions at the N-methyl-D-aspartate (NMDA) receptor complex. In the present study, we examined the effects of MK-801 and ketamine, two noncompetitive NMDA receptor antagonists, in a model of spinal cord ischemia in conscious rabbits produced by occluding the infrarenal aorta for 25 min. Five minutes after reperfusion, animals were treated with either saline, ketamine, or MK-801. By 6 h postreperfusion, all treatment groups exhibited an initial recovery of hindlimb motor function, after which the saline- and ketamine-treated groups had a similar progressive deterioration in function over the next 48 h. However, the MK-801-treated rabbits continued to recover motor function such that neurological scores in these rabbits were significantly improved relative to those of the saline-treated animals at 48 h. Histopathological evaluation showed that MK-801-treated rabbits tended to have a lesser degree of central gray matter necrosis. These results indicate that MK-801 protected against the secondary deterioration associated with this model and strengthen the potential therapeutic use of NMDA receptor antagonists in the treatment of CNS ischemia.