Objective To explore optimal suctioning negative pressure in endoscopic nasobiliary drainage (ENBD) after endoscopic retrograde cholangiopan-creatography (ERCP). Methods A total of 131 patients with extrahepatic bile duct stones complicated with infection, who were treated by ENBD after ERCP, were randomly divided into two groups according to intubation dates from September 2013 to December 2014. The patients of two groups were treated with the same medical and nursing care. The pressure of low suctioning negative pressure group (61 cases) was -1--5 kPa and the pressure of high suctioning negative pressure group (70 cases) was -5--8 kPa. The conditions of biliary bleeding, drainage volume, drainage tube obstruction and patient comfort in two groups were compared. Results There were 4 cases of bile occult blood in low suctioning negative pressure group and 9 cases in high suctioning negative pressure group (P>0. 05). The daily biliary drainage volume in low suctioning negative pressure group was (349. 79 ± 108. 26) ml, which was more than that in high suctioning negative pressure group (t=6. 76,P<0. 01). There were 8 cases of drainage tube obstruction in low suctioning negative pressure group, which was less than that of 25 cases in high suctioning negative pressure group (χ2 =8. 83,P<0. 01). There were 2 cases of postoperative vomiting and 4 cases of xiphoid under pain in low suctioning negative pressure group, which were less than those in high suctioning negative pressure group (χ2 =17. 27,3. 89;P<0. 05). Conclusions The optimal suctioning negative pressure in ENBD after ERCP is -1--5 kPa. It can be used in clinical nursing care in order to improve patient comfort and keep the drainage tube unobstructed.