Mild hypothermia and the 21-aminosteroids have both been neuroprotective in several models of cerebral ischemia. In this study we compared the effects of mild hypothermia and the 21-aminosteroid U-74389G, alone and in combination on neurologic and histopathologic outcome after temporary spinal cord ischemia. Forty male anesthetized New Zealand white rabbits were randomized to four groups (n = 10): (a) normothermia (control); (b) U-74389G (3 mg/kg intravenously [i.v.] before aortic occlusion, 1.5 mg/kg i.v. and 10 mg/kg intraperitoneally after occlusion); (c) mild hypothermia (4°C epidural temperature decrease); and (d) mild hypothermia combined with U-74389G. Spinal cord ischemia was produced by 40 min of infrarenal aortic balloon occlusion. Forty-eight hours after the procedure, the neurologic status of the animals was assessed (Tarlov score) and the animals were killed for histologie evaluation. In the normothermic control group, eight of 10 animals became paraplegic. There was a significant reduction of the incidence of paraplegia and overall neurologic deficits and a significant improved Tarlov score in the mild hypothermie group (one animal paraplegic) and in the group with both mild hypothermia and U-74389G (two animals with a mild paraparesis). The histopathologic scores showed significantly less damage in both hypothermie groups. In group 2, U-74389G administration did not improve neurologic or histopathologic outcomes. The results of the current study demonstrate that a slight decrease of intraischemic spinal cord temperature significantly improved neurologic and histopathologic outcomes after experimental spinal cord ischemia. Protection by the 21-aminosteroid at normothermic conditions, or additional protection when U-74389G was added to mild hypothermia, could not be demonstrated.