Combined total lymphoid irradiation (TLI) and cyclosporine (CyA) dramatically prolong cardiac xenografts in small animals. In order to evaluate this immunosuppressive regimen in primates, heterotopic cardiac cervical xenografts were implanted in a monkey-to-baboon model. The following groups evolved: group 1 (n = 2) control, no immunosuppression; group 2 (n = 4) CyA and steroids; group 3 (n = 2) preoperative TLI (800 rad total); group 4 (n = 4) TLI combined with CyA and steroids as in groups 2 and 3. Complement-dependent cytotoxicity, mixed lymphocyte culture, cell mediated cytotoxicity as well as myocardial biopsies were periodically monitored. A Muga scan was performed at 1 year posttransplant to assess ventricular function. Cardiac xenograft survival was best in group 4 animals (108, 184, 480, 540 days) compared with 5 and 7 days in the control group. In group 2, graft survival was 13, 17, 18 and 63 days. TLI alone prolonged survival up to 28 and 29 days. Hemorrhage and myocyte necrosis were seen in all rejected grafts of group 1, 2 and 3 animals. Mononuclear cell infiltrate and fibrosis were present in group 4 grafts at rejection. High antibody titers (1:256 to 1:512) were detected at rejection only in group 1, 2 and 3 animals. This suggests that the combined use of TLI and CyA substantially prolongs xenograft survival in a primate model by preventing early antibody-mediated rejection as well as by limiting cellular response.