In experimental models, leukemia was the first disease shown to have an association with the major histocompatibility complex (MHC) genes. In humans, several allelic human-leukocyte antigen (HLA) associations also have been recognized. In addition to allelic associations, atypical HLA segregation patterns have been observed in leukemic families. These include a higher frequency of HLA-identical unaffected siblings, increased HLA homozygosity and increased maternal HLA-DR identity. These observations suggest preferential transmission of disease-associated haplotypes and a male transmission bias in leukemic families. The lack of disease-specific segregation, however, supports the idea that the HLA system is not directly relevant in leukemogenesis. Therefore, the existence of another genetic region linked to the MHC, causing segregation distortion, and containing recessive leukemia susceptibility genes may be postulated. The mouse t-complex would fit this model. This gene complex has recessive (semi-) lethal genes, is transmitted preferentially through fathers, and both the mouse t-complex and its rat homolog, growth and reproduction complex grc, confer susceptibility to carcinogenesis. This model could also explain the increased spontaneous abortion rate in mothers of leukemic patients, epidemiologic associations of leukemia with oral clefts and neuroectodermal tumors, and the transmission of a radiation-induced leukemia risk through fathers. Such segregation distortion might be the reason behind the maintenance of a gene(s) with a lethal effect in the population.