In order to stusy the effct of defined genetic differences of one bone marrow transplantation in miniature swain, five different conninations of major histocompatibility complex (MHC)-matched adn mismatched bone marrow transplants were perfomed. Eight of nine fully MHC-mismatched allogeneic bone a marrow transplants faile to reconstitute, and one animal reconstituted briefly but then died quickly therafter. Five of six class I-matched/class II-mismatched (gc) bone marrow transplants engrafted, showed a skin rash trypical of graft-versus-host (GVH) reaction, and died 3 weeks after the marrow transplants into F 1 hosts engrafted and caused GVH skin rash, with survivals from 1 to 9 montsh (n= 5). Serologica typint of the F 1 recipients of parental marrow showed only donor-type peripheral blood lymphocytes (PBL), suggesting complete marrow replacemetnt. Conversely, F 1 into parental marrow transplants showed no engraftment (n= 6). These results indicate that resistance to MHC-mismatched allogeneic bone marrow engraftment donor class I MHC differences. This response appears to interfere with engraftment of donor bone marrow cells despionte host preparation with 900–1100 rads total-body irradiation. In the absebce of donor MHC class IO differences, engraftment was seen despite the existence of multiple non-MHC differences, and even in the presence of class II differeces. Such engraftment also led to GVH, varying in intensity according to the strength of genetic disparioty (ie, worst in parentF 1 combination). Thses results suggest that miniature swaine should proviode adn effective model for study of both GVH elimination (in the parentF 1 combination) and problems of engraftment (in the F 1 parent combination), the two most important obstacles to clinical allogeneic transplantation.