The incidence of spontaneous lung tumors in relation to H-2, the major histocompatibility complex, was studied in congenic strains of mice on the B10-, A-, and C3H-backgrounds. The most relevant results were obtained with congenic strains on the B10-background. The strains could be divided into two groups: one with a low frequency of spontaneous lung tumors carrying the haplotypes H-2b, H-2h4, H-2d, H-2iH-2r and one with a higher incidence of lung tumors carrying the haplotypes H-2f, H-2m, H-2h2, H-2a. The differences between these two groups were highly significant. Analysis of the results obtained with the recombinant strains indicated that genes in the IB region determined the susceptibility to the development of spontaneous lung tumors. The comparison of the results in the B10, B10.A and A strain has shown that the incidence in the B10.A strain carrying the haplotype H-2a derived from the highly susceptible strain A (H-2a) on the resistant background strain B10 (H-2b) is intermediate between these two strains. This shows, that other genes of the background are also involved. The lung tumor incidence in (B10.A × B10)F1 hybrids was intermediate between the two parental strains. The results obtained in the strains C3H with the haplotype H-2k, C3H.B10 with the haplotype H-2b and C3H.NB with the haplotype H-2p, were inconclusive because of the early mortality which occurred among the animals of these strains. The strains A (H-2a) and A.SW (H-H-2s) were both equally susceptible. © 1979 Springer-Verlag New York Inc.