We found that mice are susceptible to HeV infection when exposed via the intranasal route, but resist infection when challenged by a parenteral route. Infection manifested as acute, transient, and asymptomatic virus replication in the upper and lower respiratory tracts, together with clinically significant encephalitis that has a longer incubation period than is reported for other models of fulminating HeV disease. The pattern of central nervous system involvement (CNS) supports neuroinvasion by the anterograde route (spread from the neuron cell body toward the axon terminus) and, importantly, transneuronal spread within the CNS. Over all, the study demonstrated that mice are susceptible to HeV infection and has provided a new and important model for HeV induced encephalitis.