The resistance of adult mice to acute lethal infection with murine cytomegalovirus is controlled by genes linked to the H-2 complex. The k haplotype is approximately 10 times more resistant than the b or d haplotypes. Susceptibility is inherited as a completely dominant trait. At least two genes within the H-2 complex are involved, one mapping to the K/IA subregion and the other to the D subregion. The data suggest that interactions may occur between these K- and D-end genes which further affect resistance to the virus. The precise mechanism of H-2 gene control of resistance to murine cytomegalovirus remains to be elucidated. Non-H-2 linked genes also affect resistance to the virus, particularly in the C57BL genetic background, which is associated with an increased resistance to murine cytomegalovirus. Newborn mice of all strains are equally susceptible: both the H-2- and the non-H-2-associated resistances develop in the first few weeks of life and are retained up to at least 18 months of age.