AbstractA possible genetic control of the in vivo immunity to tumor‐specific transplantation antigen (TSTA) of two methylcholanthrene‐induced BALB/c fibro‐sarcomas, C‐1 and ST2, was studied in F1 compatible hosts. Both tumors, which have been previously shown to share their TSTA, lost their immunogenicity in (BALB/c×C3Hf)F1 and C‐1 also in (BALB/c×BALB.K)F1 mice; the immunogenicity of both sarcomas remained unchanged in other hybrid combinations of BALB/c with H‐2b or H‐2a animals. For C‐1 this was true either for a primary immunity to low doses (104 and 5 × 104) of tumor cells or for the secondary immune response measured as a capacity of preimmunized animals to resist a challenge of 105 cells. Since (BALB/c×B10.BR) or (BALB/c×AKR)F1 hybrids (both H‐2d × H‐2k) were able to reject C‐1 cells as strongly as BALB/c mice, the proof of a possible genetic influence involving dominant genes coding for low responsiveness to C‐1 or to ST2 and linked to H‐2k haplotype was sought in a back‐cross experiment. The primary and secondary immune response to C‐1 and the secondary immunity to ST2 were evaluated in BALB/c × (BALB/c × C3Hf) back‐cross mice. Results for both tumors were compatible with the presence of an H‐2 dominant gene (or cluster of genes), whose products suppress immunity to TSTA; the linkage of low anti‐tumor responsiveness with H‐2k was demonstrated for both C‐1 and ST2. Further evidence for this linkage was found in the study of immunity to C‐1 in (BALB/c×C3Hf)×(BALB/c×C3Hf) F2 animals. An attempt to map gene(s) governing the low immune response to C‐1 and ST2 was performed by studying the anti‐tumor immunity of BALB/c, (BALB/c×A), (BALB/c×A.TL), (BALB/c×A.AL), (BALB/c×B10.A), [BALB/c×B10.A(4R) and (BALB/c×C3H.OH]F1 mice. It was found that Kk and Dk regions are not necessary for the low immunity to C‐1 to be expressed, therefore mapping the relevant gene(s) in the Ik region. The low immune response of (BALB/c×C3H.OH)F1 mice to C‐1, however, suggested that Dk genes are also important in this phenomenon. For ST2, only BALB/c×C3H.OH animals showed a low anti‐tumor response thus mapping genes coding for a suppression of anti‐ST2 immunity in the Dk region. Since (BALB/c×B10.A) but not (BALB/c × A)F1 mice (both hybrids having an identical H‐2d × H‐2a genotype but different non‐H‐2 backgrounds) were able to develop an anti‐C‐1 immunity, an effect of non‐H‐2 factors which may counteract the suppressive activity of MHC genes is implied. The possible mechanims of this genetic control are discussed.