Prolongation of pancreas allograft survival has been difficult to achieve in rodent models despite use of immunosuppression regimens that successfully increase graft survival of other organs. The purpose of this study was to evaluate a new immunosuppressive agent, mycophenolate mofetil (MM), for its ability to prevent rejection in a rat pancreas transplant model. In addition, using congenic strains of rats, the efficacy of MM in rat pancreas transplantation was treated in the context of isolated class I or class II major histocompatibility (MHC) differences. MM in doses of 12.5 to 37 mg/kg significantly prolonged BUF to LEW heart transplant survival beyond a 14-day course of therapy thereby demonstrating its immunosuppressive efficacy. In similar pancreas transplant experiments, however, most grafts were rejected during the period of MM administration. Combination therapy with MM and cyclosporine did not extend pancreas survival beyond that achieved with MM alone (Mean Survival Time of 13.8 +/- 2.7 vs 11.7 +/- 1.6 days, respectively). Conversely, combined therapy with MM and antilymphocyte serum achieved a mean survival for BUF to LEW pancreas transplants of 52.3 +/- 24.8 days, which was significantly longer than that observed for either MM (11.7 +/- 1.6) or ALS (18.0 +/- 7.6) alone. MM therapy doubled pancreas allograft survival when used in the face of class I MHC disparity and compared to controls (19.5 +/- 1.0 vs 10.0 +/- 1.9 days) but did not prolong grafts that were disparate at only the class II locus (12.6 +/- 1.5 vs 12.0 +/- 1.2 days, respectively, for MM vs control). These data indicate that MM may not be an effective single agent immunosuppressive for pancreas transplantation except when MHC disparity is limited to the class I locus.