Orthotopic bowel transplantation continues to be a "difficult" procedure, both experimentally and clinically, despite the advent of cyclosporine. Even with high-dosage CsA administration, long-term survival has been sporadic and short-term mortality high. In the present study, a low-dosage CsA regimen (5 mg/kg/day for 2 weeks postoperatively) produced prolonged survival in BN-Lewis donor/recipient combinations utilizing an orthotopic bowel transplantation model with portal venous anastomosis. The transplanted bowel continued to survive despite the lack of maintenance dosage after initial induction. The recipient animals evinced donor-specific hyporesponsiveness as donor skin grafts were rejected in a slow, indolent fashion. Third-party skin grafts acutely rejected in normal fashion. It was remarkable that the bowel grafts continued to survive in good condition despite the rejection of donor-specific and nonspecific challenging skin grafts placed on the animals. The precise mechanism of this donor-specific hyporesponsiveness is not known.