Tracheal organ cultures were prepared from strains of mice with known susceptibility to the lethal effects of mouse cytomegalovirus. When organ cultures from susceptible mice were infected with this virus, characteristic c.p.e. developed and virus titres greater than 10(5) p.f.u./ml were produced 2 to 3 weeks after infection. Identically infected tracheal organ cultures from resistant mice consistently failed to develop significant virus c.p.e. and produced 10- to 100-fold lower titres of virus. When fibroblast cultures were infected with mouse cytomegalovirus, however, no consistent differences between susceptible and resistant mouse strains were observed. Since cytomegalovirus replicates in epithelial cells both in vivo and in tracheal organ culture, these results suggest that resistance may be based in part upon innate genetic susceptibility of epithelial cells to cytomegalovirus infection.