The first association between a disease and MHC antigens was established for viral leukemogenesis in mice. Since then, numerous studies in humans have been carried out and the data obtained suggest that Cw3 and Cw4 may be markers for leukemia susceptibility genes. Given the relatively weak relevance of HLA-C locus antigens in immune response, unrecognized properties of Cw3 and Cw4 should be considered to explain this association. Family studies have consistently revealed limited heterogeneity of HLA antigens in those families, increased parental HLA antigen sharing resulting in increased homozygosity among offspring and high frequency of recombinations within the MHC. Furthermore, the HLA genotype of leukemic patients was found more frequently among their siblings than the anticipated 25 percent. Another significant deviation from the Mendelian expectation was increased HLA-DR identity of offspring to that of their mother in those families. These and other observations imply that in leukemia families unknown MHC-linked recessive factors linked to Cw3 and Cw4 alleles may be susceptibility genes which also cause segregation distortion of HLA genes and probably developmental errors.