Background: The introduction of polymerase chain reaction (PCR) for the diagnosis of herpesvirus central nervous system infections is reshaping our understanding of these illnesses. Varicella-zoster virus (VZV) is increasingly recognized as an important etiology of sporadic viral meningoencephalitis (ME). Furthermore, mild cases of herpes simplex virus (HSV) ME, traditionally considered a devastating infection, are frequently reported., Methods: We compared the demographic and clinical features of patients with VZV (20) and HSV (17) ME diagnosed by Real-Time PCR of cerebrospinal samples in a single center during the years 2002-2010., Results: VZV and HSV patients were comparable with respect to age, sex, underlying diseases, immune suppression, and the rates of fever, headache and altered mental status on presentation. Seizures, focal neurological signs, systemic complications and in-hospital death were noted only in the HSV group., Conclusions: Our study confirms the prevalence of VZV as a cause of sporadic ME over the last decade. While patients with HSV ME had more manifestations of severe disease, there also was a significant overlap with clinical and laboratory parameters of VZV ME. In the absence of dermatomal rash, differentiation between VZV and HSV ME on clinical grounds alone may represent a true challenge., (Copyright © 2011 Elsevier B.V. All rights reserved.)