Genetic control of resistance and susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice was examined. Mice derived from various crosses between susceptible SJL (S) and resistant C57BL/6 (B6) strains allowed determination of the relative susceptibility contributed by H-2 and non-H-2 genes, as well as allowing segregation of H-2 linked genes. Six of 39 B6SF1 hybrid progeny developed disease, suggesting several possibilities--resistance is dominant and susceptibility recessive but with incomplete penetrance, the incidence of disease is dose dependent and is dictated by the number of "susceptible/resistant" alleles present at one or more loci, or some combination of the two. Data involving the progeny from the B6SF1 hybrids mated to the S parental strain indicated the involvement of more than one locus. The strong correlation between the number of H-2s haplotypes and the incidence of demyelinating disease suggested that at least one of the genes was linked to the H-2 complex; however, other independently segregating (unlinked) loci strongly affected the disease incidence among H-2 identical animals. A gene or genes from the S background was also associated with enhanced virus growth or diminished virus clearance in the central nervous system (CNS). Overall, the observations support a gene dosage model for susceptibility that relates disease incidence to the total number of S alleles at both H-2 and non-H-2 loci.