T cells present in bone marrow cell (BMC) grafts promote engraftment in histoincompatible hosts, but they or other T cells may also initiate lethal graft-vs.-host disease (GVHD). The purpose of this study was to determine whether T cells from donors tolerant of host alloantigens were able to prevent natural killer (NK) cell-mediated rejection of BMC grafts without causing GVHD. Previous studies have shown that H2d C.B-17 SCID BMC grafts were rejected by (BALB/c x B6)F1 (CB6F1,H2d/b) host NK cells, and that this rejection was reversed by adding H2d T cells to the donor inoculum. T cells tolerant of H2d/b alloantigens were produced by irradiating (3 Gy) BALB/c newborn mice, and infusing CB6F1 BMCs. Tolerance was assessed by donor (H2b+) cell chimerism, acceptance of CB6F1 skin grafts, the inability of adoptively transferred lymphocytes to initiate GVHD in irradiated CB6F1 mice, and the inability of spleen or thymus cells to generate cytolytic T lymphocytes against H2b target cells in vitro. Whole or H2-Kb-depleted BMCs isolated from tolerant donors were able to proliferate in both BALB/c and H2b/d (C57BL/6 x DBA/2)F1 hosts as determined by incorporation of a radiolabelled DNA precursor in the spleen. Furthermore, thymocytes from tolerant donors were able to prevent rejection of H2d SCID BMCs. Because the percentage of donor F1 cells was so high in these chimeras, we generated BALB/c to CB6F1 SCID BMC chimeras; the percentage of BALB/c cells was approximately 100%, the BMCs grew well in irradiated CB6F1 hosts, and their lymph node cells failed to cause a graft-vs.-host (GVH) reaction in CB6F1 hosts. Thus, GVHD may be prevented without inhibiting the ability of donor T cells to promote engraftment. Perhaps separate T cells, or separate functions of a common T cell subset, induce GVHD and enhance engraftment of stem cells.