A herpes simplex virus type 1 (HSV-1) recombinant virus deficient in the virion host shutoff (vhs) function was assessed for its ability to function as a live-attenuated vaccine. Protection of mice from wild-type challenge infection and the establishment and reactivation of HSV-1 latency was measured in a mouse ocular model. Challenge virus replication in corneas and trigeminal ganglia was significantly reduced for vaccinated mice. Consistent with these findings, the vaccinated groups showed no clinical signs during acute infection and high levels of virus-specific IgG and neutralizing antibodies were induced. The establishment of and reactivation from latency in trigeminal ganglia from the vaccinated group were also significantly reduced relative to controls. These data suggest that vhs deletion mutants may have significant utility as live-attenuated HSV-1 vaccines.