HSV infection of adult humans occasionally results in life-threatening herpes simplex encephalitis (HSE) for reasons that remain to be defined. An animal system that could prove useful to model HSE could be microRNA-155 knockout (miR-155KO) mice. Thus, we observe that mice with a deficiency of miR-155 are highly susceptible to HSE with a majority of animals (75-80%) experiencing development of HSE after ocular infection with HSV-1. The lesions appeared to primarily represent the destructive consequences of viral replication, and animals could be protected from HSE by acyclovir treatment provided 4 d after ocular infection. The miR-155KO animals were also more susceptible to development of zosteriform lesions, a reflection of viral replication and dissemination within the nervous system. One explanation for the heightened susceptibility to HSE and zosteriform lesions could be because miR-155KO animals develop diminished CD8 T cell responses when the numbers, functionality, and homing capacity of effector CD8 T cell responses were compared. Indeed, adoptive transfer of HSV-immune CD8 T cells to infected miR-155KO mice at 24 h postinfection provided protection from HSE. Deficiencies in CD8 T cell numbers and function also explained the observation that miR-155KO animals were less able than control animals to maintain HSV latency. To our knowledge, our observations may be the first to link miR-155 expression with increased susceptibility of the nervous system to virus infection.