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Intestinal transplantation is a viable treatment strategy for patients with irreversible intestinal failure for whom parenteral nutrition is no longer an option. Although improvements have been made in short-term post-transplant survival outcomes, long-term allograft loss, mainly to acute or chronic rejection, remains a major obstacle to successful transplantation. In all types of solid organ transplants, there is increasing evidence that antibodies directed against human leukocyte antigens, and in particular donor-specific antibodies (DSA), contribute to acute and chronic rejection as well as allograft loss. In this single-center review of intestinal transplant recipients, we report that the presence of pretransplant circulating DSA and the de novo induction of DSA posttransplant are both associated with increased risks of allograft loss. Although the cumulative incidence of acute rejection was not significantly affected by the presence of DSA, the power of this single-center study may be limited. Prospective, multicenter studies are needed to further elucidate the role of DSA in intestinal transplant recipients. In the published literature, there is a clear link between the presence of pre-formed DSA and early injury to the mucosal vasculature of the allograft. Two groups have reported an association between pretransplant DSA and the frequency of acute rejection episodes and subsequent graft loss. Similarly, studies investigating the effects of de novo DSA have demonstrated a relationship between the presence of post-transplant circulating antibodies and the occurrence of acute rejection and the risk of allograft failure. The use of a liver-containing graft appears to facilitate the clearance of pre-formed antibodies and prevents the de novo induction of post-transplant antibodies. The most recent report stated that the de novo induction of DSA is concurrently accompanied by signs or rejection, such that the detection of circulating antibodies may signify impending graft injury, and supports the potential utility of DSA as a non-invasive biomarker for rejection in intestinal transplantation.