Several B10 strains of mice, recombinant at the H-2 locus, have been shown to differ in their resistance to infection with ectromelia virus, a natural mouse pathogen. Of 10 strains, B10, B10.A(2R), B10.A(4R) and B10.D2 were the most resistant, while B10.G and B10.A(5R) were the most susceptible. Other strains were intermediate between these extremes. Several genes conferring resistance have been mapped to Db in B10.A(2R), Kk I-Ak I-Bk in B10.A, I-Jb in B10.A(2R) and to Dd in B10.T(6R). In general, death among susceptible strains was not a consequence of acute liver necrosis as in other non-B10 strains, and occurred randomly from 8-14 days after infection. The exact cause of death is unknown but is characterized by persisting high titers of virus in the spleen and sometimes the liver, despite an ongoing immune response indicated by strong cytotoxic T-cell activity detectable in the spleens of all mice. The most resistant B10 and B10.A(2R) strains cleared virus from the spleen and liver by 8 days after infection. Analysis of infection in chimeric mice indicates that H-2 genes, which determine susceptibility to virus persistence in the spleen, operate via radiosensitive cells of the lymphomyeloid system. This evidence, together with several examples of H-2-linked differences in cytotoxic T-cell responsiveness between resistant and susceptible strains, is consistent with the hypothesis that the mechanism by which H-2 genes control resistance to ectromelia virus in B10 strain mice is by their influence on the effectiveness of a cell-mediated immune response.