Herpes simplex virus type 1 causes an encephalitis in humans that is primarily restricted to the temporal lobe and limbic system. The distribution of lesions suggests that virus enters the brain from a single site and then spreads transneuronally to infect connected structures. Two obvious sites of potential viral entry are the olfactory and trigeminal nerves. Trigeminal nerve entry is more likely because it innervates the oral cavity, a common site of initial infection, and the trigeminal ganglion is the most common site of viral latency. In previous reports, however, experimental trigeminal nerve infection has never led to the pattern of disease observed in humans. By directly inoculating virus into the murine tooth pulp, the mandibular division of the trigeminal nerve was selectively infected. This division, which innervates the oral cavity, is the one most commonly infected in humans. Intrapulp inoculation led to an encephalitis primarily affecting the temporal cortex and limbic system. Thus, spread via the trigeminal nerve provides an explanation for the distribution of herpes simplex virus observed in the human encephalitis.