Objective Methylprednisolone (MP) is the only active drug for acute spinal cord injury (SCI), but the molecular mechanism is still further studied. To investigate the pathophysiology of SCI and the molecular mechanism of MP in treating SCI. Methods Nine rabbits were randomly divided into 3 groups, weighing (3 100 ± 140) g: sham operation group(group A, n=3), model group (group B, n=3), and drug treatment group (group C, n=3). After laminectomy was performed in3 groups, no treatment was given in group A, and the model of SCI was establ ished with modified Allen’s fall ing strike method in groups B and C at L4; then high-dose MP equivalent with human dose was adopted in group C at 2 hours after SCI and the normal sal ine in group B. All rabbits were sacrificed at 8 hours after SCI, and then the spinal cord tissues about 8 mm long which included the injuried site were obtained. Total RNA was isolated with Trizol one-step method to examine the gene expression profile by using Ogl io technologies with standard operating procedures and qual ity control as recently described respectively. GeneSpring11.0 analyzer software was used to filter potential candidate genes for statistical significance using Welch’s t test, and only genes with P lt; 0.05 and fold change (FC) ≥ 2 were retained for further analysis. Some differentially expressed genes were also verified by RT-PCR to ensure the rel iabil ity of microarray results. Results The SCI model was set up and the samples of spinal cord tissues were acquired successfully at 8 hours after SCI. The qual ify of total RNA from each group met the requirement for the microarray examination and data analysis. These differentially expressed genes involved inflammation, immunity, ion transportation, transcription factors, and so on. The results of genes IL-1α, IL-1β, and defensin 4 (NP-4) by RTPCR were consistent with that of gene-chips. The immuno-related genes included NP-3, NP-4, corticostatin 6, CAP-18, and antimicrobial peptide, which displayed obvious differential expression. Conclusion High-dose MP has protective effects on nervous function by the immunity mechanism, and the main effector may be neutrophil.