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Objective: This study investigated the proteomic characteristics of cerebrospinal fluid (CSF) in patients with varicella zoster virus (VZV) meningitis to understanding the pathogenesis of central nervous system (CNS) infection by reactivated VZV. Method: We used data‐independent acquisition model to analyze the CSF proteomic differences of 28 patients with VZV meningitis and 11 herpes zoster (HZ) patients. According to the clinical manifestations at discharge, 28 VZV meningitis patients were divided into favorable outcome group and unfavorable outcome (UO) group and their differences in CSF proteome were also analyzed. Results: Compared with the HZ group, the proteins (CXCL10, ELANE, IL‐1RN, MPO, PRTN3, etc.) related to inflammation and immune cell activation were significantly upregulated in the VZV meningitis group (p <.01). The protein related to the nerve function and energy metabolism (CKMT1B, SLITRK3, Synaptotagmin‐3, KIF5B, etc.) were significantly downregulated (p <.05). The levels of a pro‐inflammatory factor, IL‐18, in CSF were significantly higher in patients in the UO group as compared to patients with favorable prognosis (p <.05). Conclusion: Inflammatory immune response is an important pathophysiological mechanism of CNS infection by VZV, and the CSF IL‐18 levels might be a potential prognostic indicator of the outcomes of VZV meningitis. [ABSTRACT FROM AUTHOR]