Segmental small intestinal transplantation (SIT) using living related donors (LRD) is being evaluated as a therapy, clinically. Advantages of this technique include an increase in the donor pool, optimization of the timing of transplants, and potential immunologic benefits. However, the ability of a short segment of intestine to function after transplantation has not been investigated in large animal models. This study evaluates the impact of immunosuppression on the adaptive process and the ability of a transplanted segment of intestine to adapt. A pig model of segmental SIT was used. Animals were resected, leaving 150 cm of distal ileum (n = 5), resected and treated with FK506 (n = 4), or steroids (n = 4), or with FK506 + steroids (n = 7), or transplanted using a similar segment of ileum and treated with FK506 + steroid immunosuppression (n = 9). Animals undergoing resection, or resection plus steroid treatment, did well, gaining weight post-operatively (37% and 15% of preoperative weight, respectively). However, animals undergoing resection and treated with FK506 or FK506 + steroids did poorly, losing weight (-14% and -22% of preoperative weight, respectively) and showing significant impairment of intestinal adaptation, morphologically and functionally. Furthermore, FK506-treated animals developed inflammatory changes in the intestinal mucosa, mimicking rejection. Segmental SIT animals had a high rate of rejection (66%) and showed a similar impairment in adaptation. Hence, segmental SIT is a stringent physiological test of intestinal adaptation. FK506 appears to impair gut function after resection, either directly, or by interfering with the adaptive process. In this model of segmental SIT, FK506 and steroids at the doses tested did not provide adequate immunosuppression to prevent rejection and the graft did not function adequately to allow growth. Further studies are required to evaluate the mechanisms underlying these findings, and to determine if similar effects occur in humans.