Experiments with pigs have been performed in order to establish bone marrow chimerism and kidney graft tolerance between SLA genotyped semi-incompatible animals. Recipients were conditioned by means of conventional fractionated total lymphoid irradiation (TLI) delivered by a vertical cobalt source. The principal lymphoid regions of the pig, including thymus and spleen, were submitted to irradiation. Two protocols were tested: A = 250 cGy four times a week χ 13 times (TLI) (two animals) and B = 350 cGy three times a week χ 8 times (TLI) (four animals). Bone marrow cells were injected 24 hr after the last irradiation. One day later, bilateral nephrectomy and the graft of one kidney from the bone marrow cell donor were performed simultaneously. No permanent chimerism was ever obtained except for one animal in protocol A which received marrow cells contaminated with blood lymphocytes and which developed an acute lethal graft-versus-host reaction. A modification of protocol B, where the last two irradiations were administered on the whole body, was tested on three animals. It was equally unsuccessful in the establishment of chimerism. In spite of the nondetectable chimerism, a partial tolerance to a semi-incompatible kidney was obtained in two cases with protocols A and B (survival 6 months and 7 months). However, an unexpectedly high incidence of accelerated kidney graft rejection was observed in several cases (acute renal failure as early as days 4, 5, and 6 after grafting). Success or acute failure of the graft could not be explained, either by the degree of histocompatibility or by the intensity of the immunosuppression, which were roughly equal in all of the pairs tested. These results convinced us that application of the TLI protocol to humans is not yet practicable and that further experimental work is needed.