We have previously demonstrated that TNF-α levels are elevated in liver transplant patients experiencing acute rejection. In addition, prophylactic administrationof anti-TNF-α or anti-TNF-β antibodies prolonged graft survival in a rat heterotopic cardiac transplant model. This experiment was designed to evaluate anti-TNF therapy in the treatment of acute allograft rejection. Heterotopic cardiac transplants were performed using Buffalo donors and Lewis recipients. Histologic sections of transplanted grafts from untreated animals revealed significant rejection at day 4 with terminal rejection occurring on day 10.8±0.4. Animals in the experimental groups received antirejection therapy from postoperative days 4–13. Treatment with cyclosporine at 2 mg/kg/day prolonged graft survival to 16.5±2.0 days (P=0.01 versus controls). Administration of polyclonal anti-TNF-α in combination with polyclonal anti-TNF-β increased graft survival to 14.6±0.4 days (P<0.001 versus controls). Use of a monoclonal anti-TNF-α antibody was even more effective, with graft survival of 17.4±0.7 days (P<0.001 versus controls). Combination immunotherapy with monoclonal anti-TNF-α in conjunction with CsA extended survival to greater than 30 days. In contrast, recombinant TNF-α (5 μg/day, i.p.)