To study the preventive effects of double guidewire technique combined with pancreatic duct stenting in preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Patients receiving ERCP were divided into the treatment group and the control group by random number table. In the treatment group, double guidewire technique combined with pancreatic duct stenting was applied. In the control group, selective biliary intubation was applied in the conventional way. The intubation time, PEP, hyperamylasemia and bleeding incidence were analyzed between the two groups. A total of 80 patients were enrolled in this study from January 2016 to December 2018. There were 40 cases in the treatment group and 39 cases in the control group. In the treatment group, the mean intubation time was 384±102 seconds. No PEP or bleeding during and after the operation occurred, but hyperamylasemia occurred in 2 cases. In the control group, the mean intubation time was 427±115 seconds. Hyperamylasemia occurred in 6 cases, PEP occurred in 3 cases, and 1 case of intraoperative bleeding happened in the control group. The incidence of PEP [0 VS 7.7%（3/39）]and hyperamylasemia [5.0% (2/40)VS 15.4%（6/39）] were lower in the treatment group （both P<0.05). Double guidewire technique combined with pancreatic duct stenting can successfully perform selective bile duct intubation and effectively prevent PEP.