Highly metastatic, weakly immunogenic Lewis lung carcinoma clones express very low levels of H-2Kb and moderate levels of H-2Db class-I major histocompatibility complex antigens. These cells metastasize spontaneously in mice with C57BL/6 genetic background possessing the H-2Db locus, and grow as local tumors across allogeneic barriers. Transfection of the H-2Db genes into the highly metastatic clone D122 did not alter the growth or metastatic capacity of these cells in syngeneic mice. However, these cells were rejected in allogeneic mice. Transfection of the H-2Kd or H-2Kk genes into D122 elicited a CTL population that cross-reacted with cells bearing native H-2Db antigens. These data suggest that overlapping allo-CTL populations are induced by a native alloantigen and by alloantigen peptides presented through self class-I molecules.