Objective To evaluate the preventive effect of pancreatic duct stent against post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) and hyperamylasemia in high-risk patients. Methods A total of 160 patients with high-risk PEP underwent ERCP therapy between Jan. 2013 and Dec. 2014 and were retrospectively analyzed. The patients were divided into pancreatic duct stent group (n=82) and control group (n=78) according to whether receiving pancreatic duct stent or not. Abdominal pain was evaluated after ERCP. The levels of serum amylase were detected at 3 h and 24 h after ERCP. The incidences of PEP and hyperamylasemia were compared between the two groups. Results The serum amylase levels at 3 h and 24 h after ERCP in pancreatic duct stent group were significantly lower than those in control group ([184.89±257.33] U/L vs [305.35±371.81] U/L, P <0.05; [268.07±344.73] U/L vs [465.86±639.94] U/L, P <0.05). The incidences of PEP and hyperamylasemia in pancreatic duct stent group were also significantly lower than those in control group (2.4%[2/82] vs 11.5%[9/78], P <0.05;17.1%[14/82] vs 30.8%[24/78], P <0.05). The incidence of abdominal pain and abdominal pain score were (19.5%[16/82], [1.24±0.58]) in pancreatic duct stent group, which were significantly lower than those in control group (43.6% [34/78], [1.68±0.97]) ( P =0.001). Conclusion Pancreatic duct stent can effectively prevent PEP and hyperamylasemia in high-risk patients following ERCP.