Intraperitoneal infection of susceptible mice with an apathogenic herpes simplex virus type 1 (HSV-1) strain prevented the lethal outcome of a challenge infection with a pathogenic strain, even if the challenge preceded the protective infection. It was found that the protective inoculation blocks the initial replication of the challenge virus. In addition, intraperitoneal infection with the protective HSV-1 strain led to the induction of a refractory state in the central nervous system, resulting in resistance to direct intracranial infection with HSV-1. This state is also inducible locally by intracerebral inoculation of a non-replicating mutant virus. The results indicate that HSV-1 strains differing in neurovirulence may differ in the induction or the sensitivity to this protective effect. Experiments with non-replicating HSV-1 temperature-sensitive strains demonstrated that protection against lethal infection does not depend on replication or expression of late genes of the protective strain. Inoculation of animals with detergent-soluble extracts of infected cells or infected and u.v.-irradiated syngeneic cells protected the animals against co-infection with encephalitogenic challenge virus. The experiments define this protective effect as an antigen-induced-immediate host defence mechanism active within 24 h post-infection.