Human herpes virus 6 (HHV-6) is known to cause primary encephalitis in the frontal lobes/cerebral hemisphere or reactivated encephalitis in the hippocampus, but the pathogenesis remains unclear. HHV-6B has also been detected in hippocampal samples in patients with mesial temporal lobe epilepsy. A 1year and 3months old female, who had been clinically diagnosed with exanthema subitum and febrile convulsion, was found dead on the third day after onset. Macroscopic findings showed massive brain edema. Microscopic examination revealed gemistocytic astrocytes and ballooned oligodendrocytes in the frontal white matter, along with neuronal cell death with microglial infiltration in the frontal cortex. Polymerase chain reaction detected HHV-6B in the cerebrospinal fluid and necropsy brain samples. The hippocampus showed a 4-5-fold increase in virus copy number of HHV-6B compared to samples from other brain sites. Immunostaining indicated that HHV-6B had infected vascular endothelial cells, neurons and oligodendrocytes but not astrocytes or microglia. Hippocampal neurons were infected with highly concentrated HHV-6B, but the hippocampus had neither neuronal loss nor reactive glial response. Silent and abundant HHV-6B infection in the hippocampus might be associated with latent infection, reactivation and some hippocampus-oriented disorders, including mesial temporal lobe epilepsy.