Heart and heart-lung xenografts are a potential solution to the shortage of donors. Concern over the adequacy of conventional immunosuppression in prevention of xenograft rejection, however, has hindered their use. Cyclosporine has not been successful in suppressing the rejection process in cardiac xenotransplantation, and other methods of immunosuppression need to be investigated. Therefore we studied the effect of preoperative total lymphoid irradiation (TLI) in combination with cyclosporine in a primate heart-lung xenograft model using cynomolgus monkey donors and baboon recipients. Heart-lung grafts were harvested from donors and transplanted orthotopically in baboons with use of cardiopulmonary bypass. Recipients were treated in one of three groups: (1) cyclosporine and steroids (controls), (2) cyclosporine and steroids plus TLI 20 Gy, or (3) cyclosporine, steroids, antithymocyte globulin, and TLI 6 Gy. Mean survival time of the baboons treated with cyclosporine and steroids was 8 +/- 0.6 days. The group receiving 20 Gy TLI had prohibitive perioperative mortality; however, one baboon lived an additional 90 days, and at autopsy the heart showed minimal rejection. Treatment with TLI at 6 Gy in combination with cyclosporine, antithymocyte globulin, and steroids comparatively prolonged survival (16 +/- 7.8 vs 8 +/- 0.6 days; p less than 0.001), and all animals in this group died of infection, with only minimal evidence of heart rejection noted in animals surviving 30 days. We conclude that the addition of TLI and antithymocyte globulin to cyclosporine-based standard immunosuppression is a potent immunosuppressant in heart-lung xenotransplantation; nevertheless, infection remains a common complication.