When allogeneic BMT is used for the treatment of leukemia, depletion of T cells from the donor BM to avoid GVHD may be accompanied by persistence of host cells and post-transplant relapse. In this report, a murine model of MHC-compatible BMT was used to show that delayed infusion of immunocompetent donor cells early after T cell-deficient BMT eliminated residual host cells and provided an antileukemic effect without causing lethal GVHD. AKR (H-2k) recipient mice were pre-conditioned with 9 Gy total body irradiation (LD50) and transplanted with 10(7) BM cells from MHC-matched B10.BR donors. These mice did not develop GVHD and became stable, long-term mixed (donor-host) T cell chimeras. In this model, mixed or incomplete donor T cell chimerism was associated with decreased GVL reactivity. AKR hosts that were transplanted with B10.BR bone marrow admixed with 3 x 10(7) B10.BR spleen cells (as a source of T cells) became complete donor T cell chimeras, but they developed severe and lethal GVHD. However, when the infusion of donor spleen cells was delayed until 21 days after BMT, few mice exhibited any clinical signs of GVHD, and > 95% of the mice became long-term survivors. The infused spleen cells eliminated residual host T cells by 21 days after infusion, and most chimeras were able to resist a supralethal challenge with AKR leukemia/lymphoma cells. Thus, post-transplant adoptive immunotherapy with normal mononuclear cells from the marrow donor may be an effective way to eliminate residual disease or treat leukemia relapse after BMT without causing significant GVHD.