Varicella zoster virus (VZV) can cause disease in the central nervous system (CNS) during both primary infection and reactivation. Rapid and adequate diagnosis of VZV have previously been hampered by the shortcomings of standard virological methods, such as isolation and serology. Earlier reported cases of CNS manifestations of VZV infection have, therefore, mostly been noted in connection with, or shortly after, onset of vesicular rash. Several studies have recently been described of cases of VZV-induced CNS disease occurring as the only sign of viral reactivation, with the diagnosis aided by polymerase chain reaction (PCR) amplification and other methods of genome detection. A prospective study was performed using PCR on cerebrospinal fluid (CSF) and brain samples received for routine diagnosis of possible VZV infection during a 2-year period. Samples from 8 (7 from CSF, 1 from brain) of the 260 patients investigated (3.1%) were found to be positive for VZV-DNA. All 8 had a presumed reactivated VZV infection according to serological and clinical analysis. Their CNS manifestations ranged from meningitis to severe encephalitis, and only in 3 of these patients was a vesicular rash present. Thus, VZV-DNA detection in the CSF was an unexpected finding for the clinician and, in 2 cases, antiviral treatment with aciclovir was initiated only because of the PCR evidence of CNS infection. VZV should be considered as a possible causative agent of infection in patients with CNS disease of suspected viral origin, even in the absence of skin manifestations. Rapid diagnosis by PCR amplification of VZV-DNA from CSF might allow for early and adequate antiviral treatment.