OBJECTIVE To establish 2 models of long-term chronic allograft rejection (CR) of orthotopic small bowel transplantation (OSBT) using cyclosporine (CsA) or tacrolimus (FK506). METHODS F344 and Lewis rats served as donors and recipients respectively for OSBT. In the study 1, the rat was administered CsA (5 mg/kg/d) intramuscularly from postoperative day (POD) 0 to 13. In study 2, intramuscular FK 506 (0.3, 0.5, or 1.0 mg/kg/d) was delivered on POD 0-13, 20 and 27. We observed body weight gain, survival rate, and histology. RESULTS In study 1, all allografts demonstrated one or more histological features of CR but no serious villous blunting. In addition, there was no significant difference in the features of chronic allograft rejection between POD 60 and POD 90. In study 2, the rats that received FK506 at doses of 0.3 or 0.5 mg/kg/day survived to POD 126 but all died before OD 156. Recipients that were administered FK506 at a dose of 1.0 mg/kg/d survived beyond POD 180 showing the same body weight gain as the isogeneic group. Histopathologic analysis revealed distinctive features of CR in the rat models of OSBT induced by CsA or FK506. CONCLUSIONS Using CsA or FK506, we developed a rat CR model of OSBT; recipients administered FK506 survived longer and showed more classic characteristics of CR compared with those treated with CsA.