BACKGROUND: Varicella-zoster virus (VZV) central nervous system infection is typically observed in immunocompromised patients, and there is a lack of studies involving large samples of non-immunocompromised individuals. In this study, we retrospectively analyzed 108 non-immunocompromised patients diagnosed with VZV central nervous system infection. METHODS: This retrospective study was conducted in the Department of Neurology, Affiliated Nanjing Brain Hospital, Nanjing Medical University, China. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) revealed a positive result for VZV with a sequence number greater than 3, leading to a clinical diagnosis of VZV central nervous system infection. We analyzed the patients' age, gender, clinical manifestations, blood routine, erythrocyte sedimentation rate (ESR), CSF examination, magnetic resonance imaging (MRI), electroencephalogram (EEG), and Activities of Daily Living (ADL) scale scores (Barthel Index) on the day of admission and 3 month post-discharge. RESULTS: The study involved 108 patients, average age was 47.58 ± 2.91 years old (16 to 80), 33 were female (30.60%) and 75 were male (69.40%). Clinical manifestations were fever (63.9%), headache (88.9%), nausea (50%), vomiting (27.8%), fatigue (50%), dizziness (25.0%), herpes zoster (47.2%), chickenpox (0.9%), peripheral facial paralysis (19.4%), encephalopathy (5.6%), and myelitis (2.8%). The average white blood cell (WBC) count was 7.40 ± 0.48*10 CONCLUSION: VZV encephalitis in immunocompetent individuals typically presents with mild clinical symptoms and has a favorable prognosis. VZV should be considered the common pathogen in the management of patients without immunocompeted condition with encephalitis.