Isolated intestinal transplantation has been limited by poor patient and graft survival. If high survival could be achieved and if parenteral nutrition-associated liver disease were reversible, this procedure could be more widely applied, with early liver dysfunction indicating the need for transplant evaluation. Twenty-six patients who had failed parenteral nutrition received 28 isolated intestinal transplants. We analyzed patient and graft survival, the effect of sirolimus on the severity and frequency of rejection, and the reversibility of liver dysfunction after transplant. Three-year actuarial patient and primary graft survival were 88% and 71%, respectively. Two patients underwent successful retransplants. Twenty-two patients are alive at a mean of 21+/-15 (median 18; range 3-51) months. Actuarial survival with freedom from parenteral support is 81% at 3 years (21 of 26 patients). Actuarial freedom from parenteral support among survivors is 95.5% at 3 years (21 of 22 patients). Early rejection was less frequent with sirolimus (34% vs. 70% without sirolimus) (P=0.007). Moderate and severe rejection was less frequent with sirolimus (1/11 episodes vs. 9/17 episodes without sirolimus) (P=0.05). No grafts were lost after introduction of sirolimus. In all four patients with advanced liver dysfunction, fibrosis and cholestasis regressed within 1 year. High patient survival and parenteral nutrition-free survival can be achieved after isolated intestinal transplantation. Sirolimus treatment has eliminated graft loss. Parenteral nutrition-associated liver disease is reversible with intestinal transplantation. Refractory liver dysfunction in patients receiving parenteral nutrition should prompt consideration for isolated intestinal transplantation.