Abstract Objectives The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. Using a strategy to induce tolerance across strong allogeneic barriers, we have employed a brief, intensive course of immunosuppression to determine whether the induction of donor-specific hyporesponsiveness would prevent allograft rejection in a preclinical model of lung transplantation using MHC-inbred miniature swine. Methods Orthotopic left lung allografts were performed using MHC class I–disparate donors. The recipients received a 12-day postoperative course of cyclosporine ( n = 6) or a 12-day postoperative course of high-dose tacrolimus ( n = 3) as their only immunosuppression. Control animals received no immunosuppression ( n = 3). Results Cyclosporine-treated recipients exhibited graft survival ranging from 67 to >605 days. All six animals developed acute cellular rejection between postoperative days (PODs) 27 and 108. Two animals lost their grafts on PODs 67 and 69, before developing obliterative bronchiolitis (OB). The other four recipients developed OB between PODs 119 and 238. In contrast, all tacrolimus-treated recipients maintained their grafts long term, without developing chronic rejection (>339, >308, and >231). These recipients also exhibited donor-specific hyporesponsiveness in assays of cell-mediated lymphocytotoxity. All untreated control animals lost their grafts to acute rejection by POD 11. Conclusions This study demonstrates the ability of a brief course of high-dose tacrolimus to induce long-term graft acceptance with donor-specific hyporesponsiveness in a class I–disparate preclinical lung transplant model.