The aim of this study was to examine the expression and clinicopathological role of caudal homeobox 2 (CDX2) in intrahepatic cholangiocarcinoma (ICC). CDX2 expression was determined immunohistochemically in 93 patients with ICC. The association between CDX2 expression and clinicopathological features of ICC was also examined in patients with ICC. Immunohistochemical staining for CDX2 was noted in 27 patients (29.03%); patients with CDX2-positive tumors had significant survival advantages over those with CDX2- negative tumors (median survival was 40 months for patients with CDX2-positive tumors and 13 months for patients with CDX2-negative tumors; the hazard ratio was 0.36, the 95% confidence interval was 0.22-0.59, and p < 0.001). The rate of CDX2 expression was 13.46% in patients with lymphatic invasion and 48.78% in patients without lymphatic invasion (χ2 = 13.88, p < 0.01); positivity for CDX2 expression was significantly higher in patients with well-differentiated or moderately differentiated tumors than that in patients with poorly differentiated tumors (41.7% in patients with well-differentiated tumors, 47.6% in patients with moderately differentiated tumors, and 20.0% in patients with poorly differentiated tumors; Mann-Whitney U test, p = 0.01). In addition, CDX2 expression differed significantly in patients with ICC due to hepatolithiasis and patients with ICC not due to hepatolithiasis (36.51% and 13.33%, respectively, χ2 = 5.30, p = 0.02). Positivity for CDX2 expression resulted in significant survival advantages for patients with ICC. CDX2 might be used as a prognostic marker in patients with ICC.