SUMMARY The herpes simplex virus type I(HSV-1) strain ANG, unlike the majority of HSV-1 isolates, does not cause lethal encephalitis in various inbred mouse strains, when applied in doses up to 2 x 107 plaque-forming units intraperitoneally, intravenously, intravaginally, orally, or via the foot pads. We studied and compared the progress of infection by this non-lethal strain and by a lethal HSV-1 strain, and the components of the host defence mechanism involved. If injected intracerebrally, HSV-1 ANG replicated efficiently in mouse brain cells and led to encephalitis. Upon systemic or peripheral infection, it replicated in several mouse organs with a virulence similar to lethal HSV-1 isolates. It was clear that transport of HSV-1 ANG to the central nervous system (CNS) or replication in CNS tissue is efficiently restricted after peripheral infection. Conceivably, infection with lethal HSV-1 strains proceeds in two distinct steps, virus replication at the site of infection and in the spleen and, secondly, transport to CNS tissue and propagation in CNS cells. This second step is apparently blocked in infections of DBA/2 mice by HSV-1 ANG and can thus be studied separately. The blocking mechanism was not a function of interferon induction or sensitivity, nor was it due to an enhanced NK cell activation. Experiments with silica-treated mice, and with homozygous nude mice, which lacked T-lymphocytes, suggested that the observed restriction in virus transfer is independent of T-cell and macrophage functions. Yet, newborn mice were fully susceptible to intraperitoneal infection with HSV-1 ANG, suggesting that age-dependent defence mechanisms, the nature of which needs to be further examined, are of relevance in the restriction of peripheral infection by HSV-1 ANG in adult mice.