ABSTRACTH-2bmice are resistant to persistent infection of the central nervous system by Theiler's virus. They clear the infection 7 to 10 days after intracranial inoculation. Resistance maps to theH-2Dgene and not to theH-2Kgene and is associated with a potent antiviral cytotoxic T-lymphocyte (CTL) response. We usedH-2bmice in which theH-2Dor theH-2Kgene had been inactivated to dissect the respective roles of these genes in resistance. We report thatH-2D−/−but notH-2K−/−mice were susceptible to persistent infection. Furthermore, whereasH-2K−/−mice mounted a vigorous virus-specific CTL response, similar to that of control C57BL/6 mice, the CTL response ofH-2D−/−mice was nil or minimal. Using target cells transfected with theH-2Dbor theH-2Kbgene, we showed that theH-2K-restricted CTL response against the virus was minimal inH-2D−/−mice. These results demonstrate that theH-2DbandH-2Kbgenes play nonredundant roles in the resistance to this persistent infection.