Family studies in Xenopus laevis (2n=36 chromosomes) demonstrate the expression of a single major histocompatibility complex in this species. Mixed leukocyte studies in two families of Xenopus vestitus (2n=72 chromosomes) indicated that this reaction was also under the control of a single genetic region. These studies suggest that, in this polyploid species, the switch from tetrasomic to disomic inheritance has already been accomplished for this locus. In contrast, segregation of mixed leukocyte reaction determinants and patterns of graft rejection in two families of Xenopus ruwenzoriensis (2n=108 chromosomes) were incompatible with the expression of a single major histocompatibility complex, and suggest that polysomic inheritance of this locus is maintained in this species. This interpretation was confirmed by the finding in a sibship of hybrids between Xenopus ruwenzoriensis and Xenopus laevis (2n=54+18) of more than four classes of mixed leukocyte reaction-identical sibs. In laboratory-created triploid animals (trispecies hybrid among Xenopus laevis, Xenopus gilli, and Xenopus clivii), mixed leukocyte reaction and grafting experiments demonstrated that the major histocompatibility complex of each constituting species was codominantly expressed.