Previous studies of small bowel transplantation using a variety of animal models and immunosuppressive regimens have failed to demonstrate consistently prolonged survival of bowel allografts capable of maintaining a normal nutritional state. In the present study, total orthotopic small bowel transplantation was performed in inbred rat strains to determine the structure and function of intestinal allografts using cyclosporine for immunosuppression. Without cyclosporine, Lewis-Brown Norway and Brown Norway allografts were quickly rejected by Lewis recipients, resulting in host death. A 15 mg/kg dose of cyclosporine given intramuscularly immediately after operation and for 6 successive days thereafter achieved prolonged but not uniformly indefinite animal and graft survival with clinical courses and pathologic findings consistent with chronic rejection. With continuation of cyclosporine every other day until day 28, all Lewis recipients of Brown Norway allografts were alive and well 8 months after transplantation. Weight gain, maltose absorption, and multiple nutritional indices in these animals were not significantly different from those of either age-matched normal Lewis rats or recipients of Lewis isografts. Full-thickness biopsy specimens of these allografts showed no evidence of graft rejection. These results demonstrate that indefinite survival of intestinal allografts with preservation of their structure and function sufficient to allow normal growth and weight gain can be achieved with cyclosporine therapy. This success in the rat model of orthotopic small bowel transplantation suggests that clinical small-bowel transplantation may become possible using cyclosporine.