Therapeutic hematopoietic stem cell transplantation has made great strides in recent years, providing curative therapy for many previously untreatable diseases. Nevertheless, the applicability and effectiveness of this procedure continues to be restricted by adverse immunoregulatory states, including graft rejection, graft vs. host disease (GvHD), and/or persistent immunodeficiency. Here, we provide evidence that long-term hematopoietic stem cell transplantation across major histocompatibility complex (MHC) barriers is possible in the human with limited adverse sequelae. We observed the rapid, complete, and stable replacement of recipient hematopoiesis and B lymphopoiesis with donor-derived cells approximately 6 weeks following orthotopic liver transplantation for hemochromatosis. Long-term T lineage reconstitution also occurred, but most intriguingly, derived almost exclusively from expansion of mature, memory/effector T cells from the transplanted liver. Although demonstrating both functional and molecular evidence of a simplified T cell receptor (TCR) repertoire and unable to become sensitized to "new" antigens (Ag), this patient demonstrated long-term clinical immunocompetence. Moreover, the transplanted T cells were effectively tolerant to host tissues as the patient did not manifest clinically significant GvHD off immunosuppressive therapy. These observations suggest that isolated memory/effector T cell populations have the potential of promoting stem cell engraftment in an allogeneic host without persistent GvHD, and to provide sufficient immune reconstitution to provide the recipient with long-term immune homeostasis.