Objective: To investigate the risk factors for moderate to severe pancreatitis (PEP) after endoscopic retrograde cholangiopancreatography (ERCP) . Methods: Data of 6 731 patients diagnosed as having biliary and pancreatic diseases with initial papilla who underwent endoscopic retrograde cholangiopancreatography (ERCP) from June 2010 to June 2020 in the First Affiliated Hospital of Air Force Medical University were retrospectively analyzed. Parameters related to intubation and postoperative complications were prospectively collected. The main end point was moderate to severe PEP. Logistic regression was used to analyze the risk factors for moderate to severe PEP. Results: The incidence of overall PEP and moderate to severe PEP in 6 731 ERCP patients with initial papilla were 5.3% (n=359) and 1.0% (n=68) respectively. Univariate analysis showed that female, indications of ERCP , cannulation method, cannulation time, cannulation attempts, times of inadvertent pancreatic duct cannulation and cannulation without trainee involvement were associated with moderate to severe PEP (all P<0.10). Multivariate analysis showed that female (OR=2.32, 95%CI: 1.28-4.21, P=0.006), non-common bile duct stones indication (OR=2.04, 95%CI: 1.16-3.59, P=0.014), cannulation time ≥5 min (OR=2.23, 95%CI: 1.20-4.13, P=0.011), inadvertent pancreatic cannulation time ≥1 (OR=1.88, 95%CI: 1.03-3.44, P=0.040) and non-trainee involvement cannulation (OR=1.81, 95%CI: 1.02-3.22, P=0.043) were independent risk factors for moderate to severe PEP. Conclusion The independent risk factors for moderate and severe PEP include female, non-common bile duct stones indication, non-trainee involvement cannulation and difficult cannulation. Great importance should be attached to these factors above during the whole perioperative period of ERCP.