Results from studies designed to create a model of focal encephalitis caused by herpes simplex virus (HSV) are reported. Anesthetized rabbits underwent exposure and inoculation of the olfactory bulb with three different doses of a wild-type HSV. Lethal infection resulted in 69% of the animals, without evidence for a dose-response relationship. Necropsy specimens obtained on or before day 10 after inoculation routinely yielded HSV in culture. In 76% of the animals with positive cultures for virus, these cultures originated exclusively or primarily from the pyriform (or temporal) cortex and frontal lobes. Virus could not be cultured from animals killed more than two weeks after inoculation. Histological examination of brains obtained three or more days after inoculation demonstrated evidence of viral infection, with more severe involvement of temporal cortex than of the surrounding brain in 80%. Immunohistochemical demonstration of viral antigens persisted for up to three weeks after inoculation.