A CP-induced tolerance induction method in mice that consists of donor spleen cell injection followed 2 days later by CP treatment was found useful for inducing permanent skin allograft tolerance. In order to regularly overcome fully allogeneic (major H-2 plus multiminor H) barriers, both a reduction of recipient T cells with anti-T cell antibody before tolerance induction and a supplement of the spleen cells with bone marrow cells were required. The reduction of recipient T cells was necessary because the antigen-stimulated-and-proliferating cell destruction with CP, which is considered to be the main mechanism of this system, is not completed due to the less proliferative quick maturation of T cells when a relatively large number of reactive T cells exist. The bone marrow cells were required probably because the establishment of stable mixed chimerism is necessary to ensure skin graft survival. This system is considered to be potentially applicable to human transplantation.