Major histocompatibility complex class II matching is of overwhelming importance for achieving tolerance to kidney transplants (KTX) in miniature swine. When class II antigens are matched, long-term specific tolerance across complete MHC class I antigen barriers can uniformly be induced by a 12-day perioperative course of cyclosporine. This same regimen is ineffective in fully MHC-mismatched combinations. We hypothesized that initial induction of tolerance to kidney donor class II antigens by bone marrow transplantation might allow tolerance to be induced to a subsequent fully allogeneic KTX in combination with CsA therapy. We report here the results of such fully allogeneic KTX performed in 4 recipients of prior single-haplotype class II-mismatched BMT. All animals received KTX from donors class II matched to the BMT donor and received a 12-day course of intravenous CsA (10 mg/kg/day). All four animals have maintained normal serum creatinine values (less than 2.0 mg/dl) for greater than 200 days posttransplant. Specific hyporesponsiveness to both BMT and KTX donor-type MHC antigens was found in mixed lymphocyte culture and cell-mediated lympholysis assays. Compared with third-party grafts, significantly prolonged survival of BMT donor-specific (P = 0.031) and KTX donor-specific (P = 0.031) skin grafts was observed. These results demonstrate that induction of tolerance to class II antigens by BMT allows a short course of CsA to induce specific tolerance to fully allogeneic renal allografts.