Background Varicella-zoster virus (VZV) and herpes zoster cause infections of the central nervous system (CNS) manifesting as meningitis or encephalitis. As compared to enterovirus (EV) and herpes simplex virus 1 (HSV-1) and 2 (HSV-2), it is not often tested in CNS infections due to VZV and herpes zoster. There is a certain tendency to think that the findings in the cerebrospinal fluid in infections of the CNS by viruses are comparable among themselves. The exact proportion of patients with VZV primary and reactivation infection who present with lesions prior to or concomitant to its involvement in the CNS is unknown. It is also not known about the risk factors that lead to the reactivation of VZV and CNS involvement. Objective To describe the clinical characteristics and laboratory results of patients with a positive VZV polymerase chain reaction (PCR) and neurological signs and symptoms. Methods A retrospective and descriptive study was performed at the Hospital Universitario de la Pontificia Universidad Católica de Chile (Hospital Clínico UC CHRISTUS) from September 2012 to July 2014. The following parameters were recorded: neurological signs and symptoms, PCR for VZV in cerebrospinal fluid (CSF), comorbidities, personal medical history, cutaneous lesions, CSF characteristics, CNS imaging, electroencephalography (EEG), treatment, mortality, and neurological sequelae. Adult patients with meningitis, encephalitis, or meningoencephalitis due to VZV diagnosed with PCR were included. Results Out of 70 CSF samples analyzed in the previously mentioned period, 21 cases were VZV positive, 16 cases that had clinical information available were included. The mean age with VZV CNS reactivation was 47 years (range 19-80 years). Five patients (31.25%) were immunocompromised: three had human immunodeficiency virus (HIV), one had kidney transplantation, and one had primary immunodeficiency. Clinical presentation was meningitis in 11 patients (68.75%) and encephalitis in five patients (31.25%). Pleocytosis in CSF was observed in all the samples. The five immunocompromised patients had cutaneous lesions. All patients received antiviral treatment. Therapy duration was from 10 up to 21 days. The clinical course was positive in most patients and the mean hospitalization time was 15 days (range 5-60 days). No mortality was observed. Conclusions VZV is a worldwide virus and a common cause of CNS infection. The rising incidence is probably due to a better diagnostic method and a frequent clinical suspicion even in the absence of cutaneous lesions, except in immunocompromised cases, as it was observed in the present study. CNS infection presented as a wide spectrum of clinical manifestations with possible neurological sequelae. There was a reduction in neurological morbidity with antiviral therapy. Nonetheless, both the incidence and the morbidity of CNS VZV infection are expected to be diminished by varicella and herpes zoster vaccination. Additionally, there was no increase in mortality in these patients.