BACKGROUND Paraplegia remains a devastating complication for patients undergoing thoracic aortic procedures. Although surgical adjuncts have evolved to reduce the risk of paraplegia, no pharmacologic therapies have proven efficacious in attenuating spinal cord ischemia-reperfusion injury. Effects of erythropoietin in spinal cord ischemia-reperfusion injury, however, have not yet been elucidated. We hypothesized that pretreatment with erythropoietin would attenuate functional and cytoarchitectural spinal cord injury related to high-risk aortic procedures. METHODS Adult male mice were subjected to ischemia-reperfusion. Aortic arch and proximal left subclavian arteries were clamped for 5 minutes; animals were observed for 48 hours. Neurologic scores of hind limb function were assessed every 12 hours. Experimental groups consisted of treatment with erythropoietin 4 hours before crossclamping (n = 7), ischemic controls (n = 7), and sham ischemia (operation without crossclamping, n = 6). Thoracolumbar sections of spinal cord were removed after 48 hours and preserved for cytoarchitectural analysis. RESULTS Mice pretreated with erythropoietin exhibited significant preservation of hind limb motor function. All mice without pretreatment were paralyzed at 48 hours. Mice with erythropoietin pretreatment had improved motor function; 3 had no measurable neurologic deficit at 48 hours. Histologic analysis in mice treated with erythropoietin showed markedly reduced neuronal cell injury. CONCLUSIONS Erythropoeitin preserves both function and histologic appearance in mice undergoing spinal cord ischemia-reperfusion. With further elucidation of mechanisms of protection and optimal administration, erythropoietin could become an important adjunct in reducing the incidence and severity of spinal cord injury related to aortic interventions.