We have used a variety of standard inbred, recombinant, and congenic rat strains to establish the effect of MHC and non-MHC genetic incompatibilities on bone marrow transplantation. The role of these loci in the successful establishment of bone marrow engraftment was first determined by examining the potential of donor marrow to protect recipient rats from a lethal dose of the myeloablative drug busulfan. Similar donor/recipient combinations were then used to examine the effects of the same incompatibilities on the induction of fatal graft-versus-host disease (GVHD) in recipients conditioned with a combination of busulfan and cyclophosphamide. The data obtained indicate that: (1) a difference for the entire MHC of the rat is sufficient to prevent marrow engraftment and to produce fatal GVHD; (2) the class I RT1.A locus of the rat MHC has a differential effect on bone marrow transplantation, since disparity for this locus prevents successful marrow engraftment, while this gene has little effect on the development of fatal GVHD; (3) disparity for the class I RT1.E locus has no effect on bone marrow engraftment and does not stimulate GVHD; (4) disparity for the class II locus, RT1.D, can prevent marrow engraftment and elicit fatal GVHD; and (5) incompatibility for non-MHC genes can prevent the establishment of bone marrow engraftment and elicit fatal GVHD.