- The genetic control of the local growth of the Lewis lung carcinoma (3LL) and of its lung metastases was studied using inbred congenic mouse strains. The 3LL tumor, which arose spontaneously in the lungs of a C57BL/6 (H-2(b)) mouse, possesses unique but yet unknown characteristics that enable it to progress in spite of the existence of allogeneic barriers. Intrafoot-pad inoculation of syngeneic hosts with 3LL tumor cells leads to the growth of a solid tumor at the site of transplantation, followed by development of metastases in the lungs. Surgical excision of the primary tumor leads to an accelerated growth rate of pulmonary metastases and a dramatic increase in their weight and volume. We found that the local tumor grows in allogeneic mice, yet its growth rate is higher in syngeneic than in allogeneic animals. Analyzing the rate of growth of the local tumor in congenic mouse strains, it appears that it is determined slightly but significantly by the host's genetic background rather than by its H-2 haplotypes. Although the local 3LL tumor grew in all tested mouse strains, only syngeneic recipients were able to manifest metastatic growth. We found that the generation of lung metases requires compatibility at both background and H-2 haplotype. Testing the development of metastases in mice of congenic, resistant recombinant strains, we found that metastases develop only in animals that share with the tumor the gene products of the H-2D region of the MHC. Thus, metastasis formation is controlled by both a non-H-2 gene(s) and a gene(s) linked to the H-2D region. Our results show the involvement of the genetic system in the control of tumor spread and the possible significance of MHC gene products in the generation of metastases.