A 3-week-old, previously healthy infant developed biopsy-proven Herpes virus type 2 (HSV-2) encephalitis. The encephalitis was characterized by cells having intranuclear inclusions and was without evidence of inflammation or hemorrhage. Neuroimaging studies did not show any destructive lesions in the brain. In spite of antiviral therapy, the infant's neurological conditions deteriorated, and the patient died at the age of 18 weeks. Post-mortem examination showed that most of the cerebral hemispheres were replaced by multiloculated cystic cavities of various sizes, typical of multicystic encephalopathy (MCE). The cystic lesions were randomly distributed and were not confined to any vascular territory. By light microscopy, there were no features of viral infection in the brain. Although in situ hybridization of the biopsy specimen taken during the acute phase of the disease demonstrated abundant HSV genome, this same method failed to detect HSV on the post-mortem specimen. These findings suggest that HSV-2 can induce MCE. Furthermore, the absence of histological features of viral encephalitis and the failure to demonstrate viral genome in the brain at autopsy does not exclude an infectious etiology in certain cases of MCE.