BACKGROUND This study aimed to analyze the risk factors of central nervous system (CNS) infection caused by reactivation of varicella zoster virus (VZV) and provide reference for the prevention and early diagnosis of VZV-associated CNS infection. MATERIAL AND METHODS A prospective study was conducted on 1030 patients with acute herpes zoster (HZ) admitted to our hospital from January 2021 to June 2023. According to clinical manifestations and auxiliary examinations, they were divided into HZ group of 990 patients and VZV-associated CNS infection group of 40 patients. Differences in clinical characteristics and serum marker levels between the 2 groups were analyzed. RESULTS Compared with HZ group, the VZV-associated CNS infection group had a longer interval from onset to treatment, herpes mainly located in the head and neck, younger age, lower blood chloride and albumin levels, and higher levels of C-reactive protein and glutamyltranspeptidase (P<0.05, P<0.01). Logistic regression analysis found that prolonged interval from onset to treatment, herpes with craniocervical distribution, increased C-reactive protein, and decreased albumin content were independent risk factors for acute herpes zoster complicated with CNS infection (P<0.05). Combined with these 4 indicators to predict CNS infection, the AUC was 0.787, sensitivity was 64.5%, and specificity was 81.9%. CONCLUSIONS Identifying the risk factors for CNS infection caused by VZV reactivation is helpful for early screening. Clinicians should pay attention to acute HZ patients with delayed treatment, herpes occurring in the head and neck, elevated C-reactive protein levels, and decreased albumin levels. Early intervention can reduce the incidence of concurrent CNS infections.