Objective To compare the safety and effectiveness of endoscopic retrograde biliary drainage (ERBD) and endoscopic nasobiliary drainage (ENBD) in treatment of acute cholangitis. Methods A retrospective analysis was performed on data of 272 patients with acute cholangitis who underwent emergent endoscopic retrograde cholangiopancreatography (ERCP) in Beijing Chaoyang Hospital from January 2009 to June 2017. Patients were divided into ERBD group (n=143) and ENBD group (n=129) according to the drainage measures. In the ERBD group, there were 63 cases of grade Ⅰ (mild) acute cholangitis, 51 of grade Ⅱ (moderate), and 29 of grade Ⅲ (severe), and the corresponding cases in the ENBD group were 54, 37 and 38, respectively. The rate of improvement of inflammation, ERCP-related complications and interventions to drainage were compared between the two groups in all patients and each grade. Results The rates of improvement of inflammation in the ERBD group and the ENBD group were 89.5% (128/143) and 94.6% (122/129), respectively, in overall patients (χ2=2.399, P=0.126), 93.7% (59/63) and 98.1% (53/54), respectively, in grade Ⅰ patients (χ2=0.548, P=0.459), 90.2% (46/51) and 94.6% (35/37), respectively, in grade Ⅱ patients (χ2=0.125, P=0.724), and 79.3% (23/29) and 89.5% (34/38), respectively, in grade Ⅲ patients (χ2=0.657, P=0.418). The incidence of ERCP-related complications in the ERBD group and the ENBD group were 11.9% (17/143) and 7.8% (10/129), respectively, in overall patients (χ2=1.298, P=0.225), 9.5% (6/63) and 7.4% (4/54), respectively, in grade Ⅰ patients (χ2=0.006, P=0.939), 13.7% (7/51) and 8.1% (3/37), respectively, in grade Ⅱ patients (χ2=0.230, P=0.632), and 13.8% (4/29) and 7.9% (3/38), respectively, in grade Ⅲ patients (χ2=0.144, P=0.705). There were no significant differences in the rate of improvement of inflammation and ERCP-related complications between the two groups. The incidences of interventions to drainage in the ERBD group and the ENBD group were 10.5% (15/143) and 3.1% (4/129), respectively, in overall patients (χ2=5.699, P=0.017), 6.3% (4/63) and 1.9% (1/54), respectively, in grade Ⅰ patients (χ2=0.548, P=0.495), 9.8% (5/51) and 5.4% (2/37), respectively, in grade Ⅱ patients (χ2=0.125, P=0.724), and 20.7% (6/29) and 2.6% (1/38), respectively, in grade Ⅲ patients (χ2=3.965, P=0.046). There were significant differences in the incidence of interventions to drainage between the two groups in overall and grade Ⅲ patents. Conclusion ERBD and ENBD are equally safe and effective in treatment of different grades of acute cholangitis, but ENBD can reduce the incidence of interventions to drainage.