The mechanisms responsible for the difference in neurovirulence to inbred mice between two variants of the Miyama strain of herpes simplex virus type 1 (HSV-1) were studied. After intraperitoneal (i.p.) inoculation, the +GC (LPV) variant reached the spinal cord and the brain, and caused death. Conversely, the -GCr variant lacked the ability to gain access to the central nervous system (CNS) after the same route of infection and failed to kill susceptible mice. The initial virus growth after i.p. inoculation, as indicated by the number of infective centers (ICs) produced by the peritoneal exudate cells (PECs), was compared between these two variants. The virulent +GC (LPV) strain induced much more ICs than the attenuated -GCr variant. When the attenuated variant was preinoculated i.p. 24 hr before the challenge inoculation with the virulent variant by the same route, the production of ICs by the pathogenic variant was highly inhibited, and growth of this variant did not occur in the CNS. Thus, mice were protected from lethal infection by the virulent variant by preinoculation with the attenuated one. Moreover, the ability of mice to resist i.p. infection by HSV-1 was shown to be age-dependent.Herpes simplex virus (HSV) causes a number of diseases in man which may be manifestations of either acute exogenous infection or recurrent endogenous infection. (11). Defense of the host against HSV is complex and probably depends on a number of cellular and humoral factors interacting to restrict and clear the infection. The mechanisms involved can be classified as being either antigen-specific or non.-specific with respect to the ability to recognize a particular agent. The latter, i.e., natural resistance mechanisms, probably play important roles in the early phase of primary infection (13).The Miyama strain of type 1 HSV (HSV-1) was isolated in 1958 by one of the authors (17). Using two variants derived from this strain, Shimizu et al (23) compared the virulence in mice after intraperitoneal (i.p.) inoculation and found that the +GC variant was highly virulent while the -GCr variant was attenuated. We comparatively studied the in vitro cytopathology and the neurovirulence to inbred mice of five variants of the same strain and revealed that neurovirulence is positively 1259