Abstract Background: Cytomegalovirus (CMV) is a crucial pathogen in immunocompromised individuals, causing infections such as pneumonitis, colitis, and retinitis. However, research on CMV infections of the central nervous system (CNS) is limited. Objective: This retrospective cohort study enrolled patients with a CMV meningitis or encephalitis diagnosis and analyzed their underlying conditions, clinical manifestations, laboratory findings, treatments, and outcomes. Methods: The study included patients who had positive results in quantitative polymerase chain reaction (PCR) tests of their cerebrospinal fluid (CSF) for CMV at any time between January 2017 and December 2022. Clinical characteristics, laboratory findings, treatment approaches, and outcomes were reviewed and analyzed from electronic medical records. Results: The cohort comprised 12 patients with a median age of 61 years (range, 43–84 years). Stupor and generalized seizures were the most common neurological presentations. Brain imaging in half of the patients revealed nonspecific abnormalities, such as atrophy. CSF protein levels were elevated, with a median of 74.5 mg/dL. CSF pleocytosis was observed in three patients (25%) and was predominantly lymphocytic. The in-hospital mortality rate was 75% (9 out of 12 patients). Conclusions: Although rare, CMV CNS infections are associated with a high mortality rate. CSF pleocytosis is uncommon in such cases, potentially contributing to clinical misdiagnosis or underestimation. CMV meningoencephalitis should be considered in immunocompromised patients who present with unexplained seizures or altered consciousness.