BACKGROUND: Intestinal transplantation (Itx) remains the most difficult form of transplantation. This is due to the high immunogenicity of the bowel that currently obligates Itx patients to heavy immunosuppression, which causes infection, posttransplant lymphoproliferative disease (PTLD), and drug toxicity. Wider application of Itx depends on the development of tolerogenic strategies to promote engraftment while reducing the need for immunosuppression. We applied a strategy to clinical Itx that combines intraportal donor-specific blood transfusion with a deliberately low immunosuppression protocol (no high-dose steroids; lower tacrolimus level). METHODS: A 55-year-old patient received a combined liver/Itx. Donor-specific whole blood was taken from the donor during procurement and transfused in the recipient portal vein after graft reperfusion. For induction immunosuppression, no intravenous bolus of steroids was given; only two doses of anti-interleukin 2 receptor antibody were administered. The patient received posttransplantation maintenance immunosuppression with lower tacrolimus levels than average (15 ng/ml first month; 5-10 ng/ml thereafter), low-dose azathioprine (1 mg/kg first to third months; 0.5 mg/kg thereafter), and low-dose steroids (Medrol 8 mg twice daily first and second months; 4 mg twice thereafter). The patient was monitored for rejection, graft-versus-host disease, infection, and PTLD. Protocol biopsy specimens were taken from the distal ileum (2 per week). RESULTS: Clinical, endoscopic, and histologic signs of rejection did not develop. Chimerism was identified at day 28. Graft-versus-host disease was absent clinically. Chimerism was self-limiting and disappeared without modifying baseline immunosuppression and without observing a change in graft function. The patient remained free of systemic opportunistic infections, PTLD, and drug toxicity. Total parenteral nutrition was stopped at 7 weeks after transplantation. The patient remains free of total parenteral nutrition and free of rejection at 14 months after transplantation. CONCLUSIONS: We describe an Itx patient who remained rejection free despite receiving significantly lower immunosuppression than average. We hypothesize that intraoperative immunomodulation via intraportal donor-specific blood transfusion in the absence of nonspecific overimmunosuppression promoted Itx acceptance.