A33 antigen is a transmembrane protein expressed predominantly in normal intestinal epithelium and most colon cancers and cell lines. The function of A33 antigen is unclear, but indirect evidence indicates a role in cell adhesion, trafficking, and the gut immune response. The aim of this study was to determine the contribution made by A33 antigen in mediating colonic repair following colitis induction in the A33 antigen-deficient mutant mouse.Colitis was induced by treatment with TNBS/ethanol. A33 antigen-deficient or wildtype mice were sacrificed at 0, 3, 7, and 14 days after colitis induction and morphological damage, mucosal proliferation, and inflammatory cell infiltration were quantified. In a subsequent study, following the induction of colitis mice were monitored for 22 days and morbidity and mortality determined.Mice lacking A33 antigen expression were compromised in their ability to resolve TNBS-induced damage and exhibited distinct crypt pathology. In A33 antigen-deficient mice morphological damage remained unresolved at 14 days postcolitis induction. Increases in colonic cell proliferation were delayed in A33 antigen-deficient mice, and the rate of crypt fission was increased after TNBS treatment. Commensurate with these observations, polymorphonuclear cell infiltration was suppressed in the absence of A33 antigen. Mortality following colitis induction was 20% higher in A33 antigen-deficient mice than in wildtype controls.Mice deficient in A33 antigen expression show impaired resolution of hapten-induced mucosal damage, leading to increased mortality, associated with impaired epithelial cell proliferation and a suppressed adaptive immune response. This study suggests a contribution for A33 antigen in the colonic healing response following mucosal damage.