Susceptibility to some human diseases is linked, albeit weakly, to major transplantation antigens (HLA) encoded by the major histocompatibility gene complex (MHC). Here we have studied MHC/disease association in inbred strains of mice after intracerebral (i.c.) injection of lymphocytic choriomeningitis virus (LCMV). This route of infection leads to a lymphocytic choriomeningitis (LCM) which is not the result of direct cytopathic effects of the virus but is caused by the induced T-cell immune response: immunocompetent mice die whereas T-cell-deficient mice survive. By using two plaque variants of LCMV strain UBC (refs 7,8), we found that susceptibility to LCM was dependent on the LCMV strain used ('aggressive' versus 'docile' UBC-LCMV) and on the various genes of the host mouse strains. In addition, susceptibility to LCM caused by docile UBC-LCMV was clearly linked to the murine major histocompatibility locus H-2D: in MHC-congeneic C57BL/10 mice, susceptibility correlated with early onset and high activity of measurable LCMV-specific cytotoxic T cells in meninges and spleens and could be mapped to H-2D. This model shows that a severe immunopathologically mediated clinical disease in mice can be regulated directly by MHC genes of class I type and supports the notion that many MHC/disease associations directly reflect MHC-restricted and MHC-regulated T-cell reactivity.