Background In this study, the authors determined the effect of magnesium sulfate on intrathecal glutamate concentrations, hindlimb motor function, and histopathology after a transient episode of spinal cord ischemia. Methods Fifty-two New Zealand White rabbits underwent spinal cord ischemia for 30 min. Fifteen minutes before ischemia, animals received intrathecal magnesium sulfate (MgSO4) (3 mg/kg) or placebo (artificial cerebrospinal fluid). Intrathecal microdialysis samples were measured for glutamate using high-performance liquid chromatography. Neurologic function and spinal cord histopathology were assessed throughout the recovery period. Results Intrathecal glutamate levels in placebo-treated animals were higher after spinal cord ischemia compared with sham- and MgSO4-treated animals. MgSO4-treated animals had increased lower extremity motor function compared with the placebo group (64.7% vs 14.3%, P < 0.01). Histologic examination of placebo-treated animals revealed significant motor neuron cell loss at thoracolumbar levels by Day 7 (P < 0.05), whereas lower lumbar regions displayed significant neuron loss on Day 1. Spinal cords from MgSO4-treated animals exhibited less neuronal loss in lumbar regions. Similar effects were present in the thoracolumbar segments on Day 7. A significant correlation existed between diminished neuronal loss and hind leg movement (Tarlov score) and demonstrates that the neurologic outcome after MgSO4 treatment was related to lower lumbar ventral horn cell survival (r2 = 0.812, P < 0.001). Conclusions These results demonstrate that MgSO4 affords significant spinal cord motor neuron protection by diminishing acute neuronal loss at the foci of the ischemic injury (L3-L6) with delayed neuronal degeneration in adjacent spinal cord regions (T7-L2).