- Intrafootpad inoculation of syngeneic mice with Lewis lung carcinoma (3LL) cells led 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 resulted in an accelerated growth and increased incidence of pulmonary metastases. Inasmuch as 3LL tumor cells isolated from the local tumor differed antigenically from the cells isolated from the metastases, the genetic control of the local 3LL tumor growth and that of its lung metastases were tested. The local tumor grew in allogeneic mice, yet its growth rate was higher in syngeneic and semiallogeneic F1 hybrids than in allogeneic recipients. However, lung metastases did not appear in allogeneic animals. By analysis of the rate of growth of the local tumor in congenic mouse strains, the tumor progression appeared to be linked to the host's genetic background rather than to the H-2 region. The generation of lung metastases required compatibility at both background and H-2 haplotype. Tests of the development of metastases in mice of congenic resistant recombinant strains revealed that metastases developed only in animals that shared with the tumor the gene products of the D-end of the major histocompatibility complex. Thus metastasis formation was controlled by both a non-H-2 gene(s) and a gene(s) linked to the H-2D region or another nearby region to the right of H-2D.