To determine the role of TCR Vβgenes in a model of multiple sclerosis (MS), we studied Theiler's virus infection in congenic mice with deletion of TCR Vβchromosome. Congenic mice expressing the Vaβ[50% deletion of TCR Vβ] or Vcβ70% deletion of TCR Vβ] haplotype were generated in mice resistant [B10 (H-2b)], intermediate [B10.K (H-2k), B10.RIII (H-2r)] or susceptible [B10.S (H-2s), and B10.Q (H-2q)] to Theiler's virus induced demyelination. Deletion of TCR Vβgenes (Vaβor Vcβ) did not convert B10 or B10.K congenic mice to susceptibility. In contrast, congenic B10.RIII-Vcβdeveloped prominent demyelination and 10-to 100-fold increase in virus-antigen expression in spinal cord compared to B10.RIII mice. No effect on the extent of demyelination was observed in B10.S-Vaβ, B10.S-Vcβor B10.Q-Vcβmice. These experiments illustrate the critical interactions between MHC, TCR, and background genes in susceptibility to immune-mediated disease.