Graft-versus-host disease (GVHD) is prominent in irradiated hosts given whole allogeneic bone marrow cells but is generally undetectable when T-depleted stem cells are transferred; under these conditions, the mature T cells arising from the donor stem cells become tolerant to host antigens and fall to cause GVHD. We show here that a radically different situation can occur when hosts are reconstituted with xenogeneic stem cells. When lightly irradiated, adult C.B-17 SCID mice injected with Lewis rat fetal liver (FL) cells show near-total repopulation with rat-derived lymphohemopoietic cells, including T and B cells. However, in marked contrast to chimeras prepared with allogeneic mouse FL cells, rat FL-->SCID chimeras develop severe and often lethal chronic GVHD. In these rat-->mouse chimeras, the rat T cells show limited tolerance to host mouse antigens as determined by various parameters including mixed lymphocyte reaction and cytotoxic T lymphocyte assays in vitro, adoptive transfer of T cells to secondary SCID hosts, and the lack of V beta deletion to endogenous host mtv antigens. GVHD in irradiated rat-->SCID chimeras is most prominent with Lewis FL but also applies to Fisher 344 and Wistar Furth FL cells. The failure of newly formed rat T cells in rat-->SCID chimeras to become fully tolerant to host mouse antigens appears to be due to depletion of host antigen-presenting cells by irradiation. Thus, rat-->SCID chimeras generated by transplanting rat FL cells into unirradiated neonatal SCID mice fail to develop GVHD, and the rat T cells display self-tolerance. As allogeneic H-2-different mouse FL-->irradiated SCID chimeras display strong self-tolerance, presumably through recognition of host antigens on thymic epithelial cells, the implication is that mouse thymic epithelial cells are tolerogenic only for mouse and not for rat immature T cells.