Intracerebral infection of susceptible SJL/J (H-2s) mice with the Daniel’s strain of Theiler’s murine encephalomyelitis virus produces chronic, progressive, inflammatory central nervous system demyelination, with minimal spontaneous remyelination. To assess the role of host genetic factors in spontaneous myelin repair following chronic infection with the Daniel’s strain of Theiler’s virus, we examined demyelination and spontaneous remyelination in strain A mice after infection with Theiler’s virus. We found that A.BY/SnJ (H-2b) mice were resistant to Theiler’s virus-induced demyelination, whereas A/J (H-2a), A/WySnJ (H-2a), and A.SW/SnJ (H-2s) mice all developed chronic demyelination with substantial spontaneous remyelination 90 days after infection. In the spinal cords of both A/J and A/WySnJ mice, one quarter of the total lesion area showed spontaneous remyelination, whereas in A.SW/SnJ mice, the extent of remyelination increased to two thirds of the total lesion area. The spontaneous remyelination seen in strain A mice was consistent with myelin repair by oligodendrocytes and Schwann cells, and occurred despite the presence of persistent virus antigen. These results indicate that host-pathogen interactions play an important role in myelin regeneration after virus-induced demyelination, and suggest that host genetic factors influence spontaneous remyelination.