BACKGROUND Graft injury incurred during periods of cold storage remains a factor affecting the success of small bowel (SB) transplantation. No one preservation solution, including the gold standard University of Wisconsin (UW) solution, has been able to maintain graft integrity for storage periods paralleling that of other commonly transplanted intra-abdominal organs. We investigated the role for the luminal administration of preservation solutions in a small animal model, documenting significantly improved graft quality. The current study addresses direct clinical applicability using human SB. METHODS Human SB was obtained at the time of standard multiviscera procurement. After a common intra-arterial UW flush, the SB was immediately removed from the abdomen, randomly divided into three segments, and treated as follows (n=6-9): group 1, no luminal flush; group 2, luminal flush with UW solution; and group 3, luminal flush with an amino acid- enriched solution. Analysis of cellular energetics, permeability, and histologic injury was performed throughout 24 hr of cold storage. RESULTS Mucosal barrier function, measured by mannitol permeability, was significantly better overall in groups 2 and 3, with 24-hr values measuring 31 and 34 nmol/cm2/hr versus 57 nmol/cm2/hr, respectively (both P<0.05). Significantly less morphologic injury was also noted in the luminally treated specimens (groups 2 and 3) compared with the clinical standard (vascular flush with UW solution). Damage in group 1 reached gross villus denudation with an obvious elevated risk of villus tissue loss, whereas groups 2 and 3 only exhibited epithelial clefting to varying degrees. CONCLUSIONS This study supports luminal administration of preservation solutions for improvement of human SB graft quality during clinically relevant periods of cold storage.