Adult athymic Nu/Nu mice showed increased susceptibility to lethal infection with murine cytomegalovirus (MCMV) when compared to their heterozygous T cell-competent Nu/+ littermates. The extent of this increase in susceptibility varied dramatically depending on the genetic background of the mice carrying the Nu/Nu gene. Genetically susceptible Balb/c (H-2d) mice showed a > 316-fold difference between the LD50 of Nu/Nu and Nu/+ littermates. The genetically resistant CBA (H-2k) strain was characterized by only a 16-fold difference in resistance between Nu/Nu and Nu/+ mice and the athymic CBA Nu/Nu mice were no more susceptible than the T cell-competent Balb/c Nu/+ strain. Thus, the (H-2k)-associated resistance of the CBA strain apparently is mediated by non-T cell-dependent early defense mechanisms.