Objective To explore the clinical application in the prevention of post-ERCP pancreatitis (PEP) for high-risk patients undergoing endoscopic duct stent placement. Methods The clinical data of 112 patients with high-risk PEP between January 2005 and June 2010 in this hospital were analyzed retrospectively. According to stents placement or not, 112 patients were divided into stent placement group (n=52) treated by ERCP and stents placement and non-stent placement group (n=60) treated by ERCP without stent retaining. PEP was diagnosed according to Cotton standard, the incidence rate of PEP was compared between two groups and the high-risk influencing factors were analyzed. Results According to Cotton standard, there were only 3 patients (5.8%) diagnosed PEP in the stent placement group, all symptoms disappeared on 48 h after operation, without a diagnosis for severe acute pancreatitis. There were 9 patients (15.0%) diagnosed PEP in the non-stent placement group, and 2 patients were severe acute pancreatitis, The status was better undergoing fasting, aprotinin, anti-inflammatory, and enteral nutrition supporting treatment. The incidence of PEP was associated with younger women (age ≤45 years), Oddi sphincter dysfunction, and no dilation of bile duct (Plt;0.05). Conclusion It can obviously reduce PEP occurrence in high-risk patients with stent placement.