SUMMARYAs a part of our development of the rabbit as a model system for transplantation, we investigated the genetic factors influencing the reaction levels obtained in rabbit mixed leukocyte cultures. Inbreeding strains and noninbreeding rabbits that were serologically characterized for their major histocompatibility complex (MHC) were compared for their levels of response in reciprocal unidirectional semimicro mixed leukocyte cultures. Tests between inbreeding or noninbred rabbits that were identical for their serological determinants showed weak or no cross-stimulation; this confirmed our earlier findings which show that the mixed leukocyte culture response in the rabbit is governed by a locus (RLD) which is an integral part of the major histocompatibility complex. Cultures of cells from rabbits with distinct MHC haplotypes demonstrate varying levels of response which, in one-way reactions, is controlled primarily by the particular allelic combinations of the stimulating and responding cells. By comparing the responses of rabbits from two separate sublines which were identical for their MHC serological and lymphocyte-defined determinants, we have found evidence for a locus independent of the MHC, which influences the magnitude of the response toRLD-mismatched stimulators. Weak reactions have been observed between certain donor combinations that have identical RLA haplotypes; these may represent the contribution of minor loci to the reaction levels. Mixed leukocyte reactions between homozygotes having nine distinct MHC haplotypes show that these haplotypes may be arranged into mutually nonreactive subsets. This suggests a restricted polymorphism of theRLDalleles, compared to the serological polymorphism in our colony.