Following infection with lymphocytic choriomeningitis virus (LCMV), normal adult mice generate virus-specific, major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTL) which clear the virus after intraperitoneal infection or cause death following intracranial (i.c.) infection. We have investigated the response of β2-microglobulin-deficient (β2m-) mice of the H-2(d) haplotype (KOD mice) to LCMV infection. Unlike H-2(b) β2m- mice, which generate CD4+ MHC class II-restricted CTL in response to LCMV, KOD mice generate high levels of CD8+ MHC class I- restricted, virus-specific CTL. These CTL are specific for the LCMV nucleoprotein epitope (residues 118 to 126) in association with the L(d) class I molecule, analogous to the CTL response in wild-type mice. KOD mice are also susceptible to lethal LCM disease, with 75 to 80% of the mice dying 7 to 9 days following i.c. infection with virus. Similar to results with normal mice, lethal LCM disease in KOD mice is prevented by in vivo depletion of CD8+ T cells prior to i.c. infection. In contrast to wild-type mice, however, KOD mice cannot control LCMV and become persistently infected. Overall, these results demonstrate that β2m is not an absolute requirement for presentation of endogenous antigen on L(d) or for induction of virus- specific L(d)-restricted CTL in vivo.