OBJECTIVE To evaluate the pharmacokinetics of high-dose methylprednisolone in patients with acute spinal cord injury (ASCI). METHODS Open-label study of consecutive patients with ASCI, and retrospective review of able-bodied controls. METHODS Emergency Medicine Department of a large, urban, university-affiliated, tertiary care trauma center. METHODS Eleven men with ASCI. METHODS Methylprednisolone sodium succinate 30 mg/kg intravenous bolus, followed by 5.4 mg/kg/hour for 23 hours, administered according to the second National Acute Spinal Cord Injury Study (NASCIS 2) protocol. RESULTS The total systemic clearance of methylprednisolone was significantly less in acutely injured patients (mean +/- SD 30.04 +/- 12.03 L/hr) than in historically reported able-bodied controls (44.70 +/- 4.90 L/hr). An inverse correlation between the neurologic level of injury and systemic clearance was seen. No differences in volume of distribution were discernible between patients (126.90 L) and controls (135.45 L). CONCLUSIONS Patients with acute spinal cord injury administered methylprednisolone according to the NASCIS 2 protocol had an apparent decrease in total systemic clearance of the drug without a commensurate change in volume of distribution. Additional studies are warranted to confirm these findings and assess the potential impact of diminished clearance on the efficacy of the agent in ASCI.