In optimal seasonal conditions, outbred adult snakes Psammophis sibilans displayed the major immunological functions related, in mammals, to the presence of the major histocompatibility gene complex (MHC). Thus, out of 30 snake random pairs that exchanged skin transplants 72.9% rejected their allograft in an acute or subacute manner. Strongly significant proliferative response was recorded in 67.3% of 168 separate one-way mixed leukocyte reaction (MLR) cultures. Lymphocytes from 6/11 snakes immunized by skin allografting displayed, after secondary stimulation in vitro, cell-mediated lympholysis (CML) in vitro of 51Cr-labeled lymphoblasts derived from the donor snake. Finally, cytotoxic alloantibodies were readily generated after snake priming with skin allograft and blood cells. Snakes did not only exhibit the major cell- and humoral-mediated immune functions, but these functions appeared to be linked with the degree of MLR disparity. Thus, animals with different MLR rejected skin allografts acutely and produced cytotoxic effector cells. In contrast, MLR-identical animals rejected the skin allograft of their partner chronically and failed to produce killer cells in CML. This significant positive correlation between MLR disparity, graft rejection and CML suggests that the responsible antigens are encoded, as in other vertebrates, by the same genetic system, the MHC.