Antagonism of N-methyl-D-aspartate (NMDA) excitatory amino acid receptors limits tissue damage after experimental cerebral ischemia. Spinal cord trauma leads to a progressive decline in blood flow that is associated with secondary tissue damage. In the present studies, we evaluated the hypothesis that NMDA receptor activation contributes to the pathophysiology of spinal cord injury by examining the effects of the NMDA antagonist MK801 after impact trauma to rat thoracic spinal cords. MK801, in doses of 1.0 and 5.0 mg/kg administered intravenously (IV) at 15 min after trauma, improved long-term neurologic recovery. At a dose of 1.0 mg/kg, the drug reduced histologic changes as well as alterations in certain tissue cations found after spinal trauma. These findings suggest that excitotoxins contribute to the pathophysiology of spinal cord injury and that early treatment with NMDA antagonists may reduce posttraumatic tissue damage.