Although CDX2-mediated intestinal metaplasia and its association with gastric and esophageal carcinoma have been well described, its function in extrahepatic bile duct (EBD) carcinoma remains unclear. CDX2 and MUC2 expression were examined in 193 EBD carcinomas, and observed in 37.3% and 42.0%, respectively. Both CDX2 and MUC2 were observed in 27.4%. CDX2 (P<.001) and MUC2 (P<.001) were correlated with histologic subtypes and present, respectively, in all intestinal-type adenocarcinomas and mucinous carcinomas, 12 (71%) and 13 (76%) of 17 papillary carcinomas, 2 (40%) and 2 (40%) of 5 adenosquamous carcinomas, and 28.4% and 33.5% of adenocarcinomas, not otherwise specified. CDX2 was observed more frequently in tumors with papillary growth (P=.03) and no vascular invasion (P=.04), whereas MUC2 was more common in cases with low stage (P=.01) and no vascular invasion (P<.001). Patients with CDX2+/MUC2+ tumors had significantly better overall survival in univariate but not multivariate analysis than patients with other tumors (P<.05). Expression of CDX2 and MUC2 supports that intestinal differentiation is present in specific subtypes of EBD carcinomas, and their expression status correlates with patients' overall survival.