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Purpose: S100B protein is widely used as a measure of glial activity or damage in several brain conditions. Central nervous system (CNS) infections can cause neurological sequelae because of parenchyma invasion. It is difficult to predict further neuronal damage in the CNS infection. The present study is aimed to evaluate the role of the cerebrospinal fluid (CSF) S100B protein as an indicator of neuronal damage in CNS infection. Materials and Methods: We measured the concentration of CSF S100B protein in 62 patients with a CNS infection using an Enzyme-Linked Immunosorbent Assay. The patients with CNS infections were classified as having no neuronal damage (CNS-N) or as having neuronal damage (CNS+N) according to the presence of neurological change or structural lesions on brain MRI. Results: The CSF S100B protein level of the CNS+N group (n=22, 0.235 μg/L, 0.10-2.18) was significantly higher than that of the CNS-N group (n=40, 0.087 μg/L, 0.06-0.12) and control group (n=40, 0.109 μg/L, 0.07-0.14, p<0.01). Using an arbitrary cut off value, S100B-positive CSF was detected in 2.5% of the CNS-N group and in 50% of the CNS+N group (p<0.05). Conclusion: These findings suggest that increased S100B protein levels in the CSF may be associated with the neuronal damage following CNS infections.