CD44 is a widely expressed cell surface protein that recognizes multiple ligands and is involved in extra- and intercellular adhesion. The precise role of CD44 in immune interactions is currently unknown, but it is believed to be a homing receptor involved in lymphocyte trafficking and inflammatory responses. This study investigated CD44 expression in intestinal tissue after heterotopic rat small bowel transplantation and assessed the effect of transplantation on intestinal epithelial cell proliferation using an antibody to the nuclear activation Ag Ki67. Lamina propria and intestinal epithelial cell expression of CD44 was graded blindly by five observers, and villus epithelial cells were noted as being positive or negative for Ki67 staining. CD44 expression was high in the lamina propria of both allografted and isografted animals; however, there was no significant difference between the two groups. In contrast, the expression of CD44 on the villus epithelium was greater in allografted animals and progressed toward the villus tips as rejection developed, declining thereafter because of loss of villus integrity. Ki67 positivity was also greater in allografted animals but did not progress toward the villus tip. This is the first reported observation of CD44 expression on intestinal epithelium that is not restricted to the crypts. The findings indicate the involvement of CD44 in the rejection process and demonstrate changes in the proliferative profile of rejecting small intestinal epithelium. Further studies into adhesion molecules, such as CD44, may help to improve understanding of graft failure and promote the development of new therapeutic approaches for controlling and preventing graft rejection.