Objective To compare the clinicopathological features of hilar cholangiocarcinoma (HCCA) and hilar benign diseases, and then explore the value of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) in the differential diagnosis between them. Methods Clinical data of 65 patients (54 patients with HCCA and 11 patients with hilar benign diseases) who were diagnosed as HCCA and received treatment from January 2011 to October 2015 in our hospital were retrospectively analyzed. Comparison of clinical data of HCCA patients and patients with hilar benign diseases in age, gender, disease duration, clinical manifestation, laboratory examination, and imaging examination was performed, and the receiver operating characteristic curve (ROC) was used to explore the value of CA19-9 and CEA in differential diagnosis between hilar benign diseases and HCCA. Results The age, levels of serum CA19-9, CEA, alanine aminotransferase (ALT), total bilirubin (BILT), and direct bilirubin (BILD) of HCCA group were significantly higher than that in benign group (P<0.05). However, the gender, disease duration, clinical manifestations (including jaundice, abdominal discomfort, fever, and weight loss), serum aspartate aminotransferase (AST), serum alkaline phosphatase (ALKP), and imaging findings (including hilar mass, intrahepatic bile duct dilatation, thickening of the bile duct wall, lymph node enlargement, vascular invasion, and gallbladder invasion) had no significant difference between the 2 groups (P>0.05). The ROC curve results showed that, when cut-off point for CA19-9 was 233.15 U/mL, the sensitivity was 56% and specificity was 91%; when cut-off point for CEA was 2.98 ng/mL, the sensitivity was 61% and specificity was 90%. Conclusions For the differential diagnosis between HCCA and hilar benign diseases, the elderly patients with high levels of serum transaminase and bilirubin were more likely to be malignant. It is more likely to be malignant when the serum CA19-9>233.15 U/mL or CEA>2.98 ng/mL.