Background.The requirement for potent systemic immunosuppression to prevent intestinal graft rejection has resulted in high rates of infection and posttransplant lymphoproliferative disease. Budesonide (BUD) is a locally acting steroid that is almost completely metabolized during its first pass through the intestinal wall and liver. The present study examined whether BUD could prevent small bowel allograft rejection without causing the adverse systemic effects associated with prednisolone.Methods.Orthotopic Brown Norway to Lewis rat small bowel allotransplants were randomly assigned to treatment with low-dose BUD (0.1 mg/kg/day, p.o.) and high-dose BUD (1.0 mg/kg/day, p.o.) with and without cyclosporine (CsA; 2 mg/kg/day s.c.). The following parameters were assessed: allograft survival, recipient plasma adrenocorticotrophic hormone (ACTH) levels, recipient adrenal, splenic and thymic weights, recipient CsA levels, and graft histopathology.Results.Low- and high-dose BUD alone did not prolong graft survival compared with the untreated group (9.1±0.4 days vs. 11±0.8 days vs. 9.7±0.4 days, respectively). However, when low-dose BUD and high-dose BUD were given in combination with CsA, the mean graft survival times were prolonged to 27.6±5.3 and 36.6±8.0 days, respectively (P<0.01). ACTH levels, adrenal weights, and thymic weights were not significantly different in the treatment and control groups receiving intestinal transplants.Conclusions.BUD enhances the immunosuppressive effects of CsA and prolongs small bowel allograft survival in rats without inhibiting normal ACTH release. These data suggest that BUD may be a useful immunosuppressive agent for clinical intestinal transplantation.