BACKGROUND The correlation between serum concentration of neuron specific enolase (NSE), S100B, and the prognosis of patients with acute spinal cord injury (ASCI) remains controversial. MATERIAL AND METHODS Sixty patients with confirmed diagnosis of ASCI were recruited for this study from February 2015 to January 2017. The serum level of NSE and S100B were dynamically measured: on the day of injury and for 2 weeks. The 60 cases were divided into Group A (1 or more than 1 ASIA grade improved at 6 months after the injury) and Group B (ASIA grades changed <1 at 6 months after the injury). The serum level of the 2 groups were compared at different time points. And the prognostic value of serum NSE and S100B as biomarkers in patients with ASCI were calculated by Bayes theorem. RESULTS The serum levels of NSE in Groups A and B on the 2nd day of injury reached a peak at 66.80±13.76 g/L and 98.87±20.12 μg/L, respectively, and then declined gradually. On the 14th day of injury, the serum levels of NSE in both groups were 21.23±8.45 and 39.32±16.31 μg/L, respectively, which were much lower than those on the 2nd day (P<0.05). The serum levels of S100B in Groups A and B rose after the injury and reached a peak on the 4th day of injury. Then, the levels declined gradually to 1.14±0.64 and 1.97±0.98 μg/L, respectively, 2 weeks after the injury. Serum levels of NSE and S100B were good biomarkers for predicting the prognosis of ASCI patients with the sensitivity of 74.35% and 71.79%, the specificity of 71.43% and 66.67%. The cutoff value for serum NSE and S100B were 29.07 μg/L and 1.67 μg/L respectively. The AUCs were 0.78 (95% CI: 0.66-0.89) and 0.76 (95% CI: 0.63-0.89) respectively for serum NSE and S100B. CONCLUSIONS Serum levels of NSE and S100B protein can reflect the degree of spinal cord injury and could be potential biomarkers for the prognosis of acute spinal cord injury.