The clinicopathological and prognostic significance of CDX2 and mucin expression have not been comprehensively evaluated in small intestinal adenocarcinoma. Immunohistochemical microarray analyses of CDX2, MUC1, MUC5AC, and MUC6 protein expressions in 189 surgically resected small intestinal adenocarcinoma cases were examined and compared with various clinicopathologic variables, including survival. CDX2, MUC1, MUC5AC, and MUC6 expressions were observed in 43.4% (82 patients), 37.6% (71), 31.7% (60), and 21.7% (41) of patients, respectively. Whereas CDX2 expression was found to be associated with low-grade tumors (P=0.034), fewer nodal metastases (P=0.019), and less perineural invasion (P=0.049) in small intestinal adenocarcinoma patients, patients expressing MUC1 tended to demonstrate high-grade (P=0.021) and nodular or infiltrative (P=0.020) tumors. On the basis of the combined CDX2, MUC1, MUC5AC, and MUC6 expression patterns, small intestinal adenocarcinoma patients were further classified as intestinal (CDX2+/MUC1-; 29.6%), pancreatobiliary (CDX2-/MUC1+; 23.8%), mixed (CDX2+/MUC1+; 13.8%), gastric (CDX2-/MUC1-/MUC5AC+ or MUC6+; 13.8%), or null (CDX2-/MUC1-/MUC5AC-/MUC6-; 19.0%). Among these immunophenotypes, intestinal-type patients demonstrated more frequent distal (jejunal or ileal; P=0.033), tubular (P=0.039), and low-grade tumors (P=0.004) and significantly better survival according to univariate (P<0.0001) and multivariate (P=0.001) analyses. In summary, intestinal immunophenotype adenocarcinomas are associated with distal (jejunal or ileal), tubular, and low-grade tumors and better survival outcomes. Hence, CDX2 and mucin immunohistochemical staining may provide better estimations of survival after surgical resection and intestinal immunophenotype could therefore be used as a better prognostic indicator of small intestinal adenocarcinoma.