Background. The ability of T cells from pigs, the most suitable donors for clinical xenotransplantation, to induce graft-versus-host disease (GVHD) and to facilitate hematopoietic cell engraftment in highly disparate xenogeneic recipients remains unclear. In this article, the authors address these questions in a presensitized pig-to-mouse transplantation model using porcine cytokine-transgenic mice. Methods. Swine donors were presensitized by mouse skin grafting and boosted by the injection of mouse cells after the skin graft was rejected. Porcine peripheral blood mononuclear cells (PBMC) and splenocytes were collected at various times after mouse skin grafting, and their potential to induce GVHD and to facilitate donor hematopoietic cell engraftment in conditioned murine recipients was evaluated. Results. Presensitization of donor pigs resulted in marked enhancement of anti-mouse responses, as reflected in augmented anti-mouse mixed lymphocyte responses, cell-mediated cytotoxicity, and antibody production. However, injection of high numbers of PBMC and splenocytes (>1×108) with bone marrow cells from the presensitized pigs failed to induce detectable GVHD or long-term chimerism in mice that were treated with depleting anti-T-cell and natural killer cell antibodies, cobra venom factor, medronate-liposomes, and 4 Gy of whole-body and 7 Gy of thymic irradiation. Histologic analysis revealed no mononuclear cell infiltration or GVHD-associated lesions in the liver, intestine, lungs, or skin of the mouse recipients. Furthermore, the recipient mice had no detectable T cells or anti-pig immunoglobulin G antibodies in the blood by 6 weeks after injection of porcine cells. Conclusion. These results demonstrate that porcine T-cell function is severely impaired in the xenogeneic murine microenvironment.