Objective To evaluate radiography with CO2 combined with contrast agents for endoscopic drainage of unresectable hilar cholangiocarcinoma. Methods Clinical data of 43 patients with unresectable hilar cholangiocarcinoma undergoing endoscopic drainage in the First Hospital of Lanzhou University from October 2010 to October 2015 were analyzed retrospectively. According to different contrast agents in radiography, patients were divided into the study group (CO2 combined with contrast agent) and the control group (contrast agent alone). There were 23 cases in the study group and 20 cases in the control group. Total postoperative bilirubin(TBIL), white blood cell(WBC), procalcitonin (PCT) and the incidence of complications in the two groups were compared. Results The endoscopic procedure ranged from 50 min to 70 min. TBIL, WBC, PCT at 48 h and 72 h after operation in the study group were lower than those in the control group[48 h TBIL：（173.42±66.78）μmol/L VS（210.81±78.34）μmol/L, P=0.025; 72 h TBIL:（104.64±56.35）μmol/L VS（159.33±59.59）μmol/L, P=0.023；48 h WBC:（11.51±7.78）×109/L VS（15.83±6.67）×109/L， P=0.026; 72 h WBC:（10.92±5.64）×109/L VS（14.72±4.97）×109/L, P=0.026; 48 h PCT:（0.56±0.18）ng/mL VS（1.24±0.73）ng/mL，P=0.003; 72 h PCT:（0.42±0.27）ng/mL VS（0.90±0.20 ）ng/mL, P=0.001]. The incidence of postoperative cholangitis in the study group was lower than that in the control group [13.0%(3/23) VS 40%(8/20), P=0.043]. Relatively low incidence of postoperative pancreatitis occurred in both groups, with no significant difference [4.3%(1/23) VS 10.0%(2/20), P=0.090]. Conclusion: Radiography with CO2 combined with contrast agents during endoscopic drainage procedures for unresectable hilar cholangiocarcinoma is safe and effective, which could lower incidence of postoperative cholangitis.