Aim:This study used an experimental rabbit spinal cord ischemia-reperfusion injury (SCIRI) model to examine the effects of amantadine, a drug with neuroprotective and anti-inflammatory activities, on oxidative stress, tissue necrosis, apoptosis, and neurological recovery.Material and Methods:Rabbits were randomized into five groups: control, ischemia, vehicle, methylprednisolone (MP), and amantadine (AMT). At 24th-hour neurological examination was performed, spinal cord tissue was collected and biochemical and histopathological examinations were performed. Results:When ischemia and vehicle groups were compared with control group, significant increase was seen in serum and tissue caspase-3, malondialdehyde (MDA), and myeloperoxidase (MPO) levels (p<0.001); significant decrease was seen in serum and tissue catalase (CAT) levels (p<0.001); and significant increase was seen in serum xanthine oxidase (XO) levels (p<0.001). When the ischemia group and the MP and AMT groups were compared, low serum and tissue caspase-3 levels (p<0.001), high serum and tissue CAT levels (p<0.001), significantly low serum XO levels (p<0.001), low serum and tissue MDA levels (p<0.05) and tissue MPO levels (p<0.001) were found. Both AMT and MP groups showed decreased histopathological score and higher number of normal neurons (p<0.001) compared to ischemia group. Both AMT and MP showed better modified Tarlov scores compared to the ischemia group (p<0.001).Conclusion:In this study we demonstrated, for the first time in the literature, the antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects of AMT on SCIRI using biochemical, microscopic, and ultrastructural techniques. AMT might be a candidate medication for SCIRI prophylaxis and treatment.