Background: Pancreatic stenting effectively lowers the occurrence of post-ERCP pancreatitis (PEP) and reduces its severity. However, limited research has been conducted to determine the optimal timing for pancreatic stent placement. Our objective was to evaluate whether early pancreatic stent placement (EPSP) is more effective than late pancreatic stent placement (LPSP) in preventing PEP among patients with naive papilla. Methods:We conducted a retrospective cohort study that analyzed 590 patients with difficult biliary cannulation using the pancreatic guidewire technique, who were grouped into EPSP and LPSP. In the EPSP group, a pancreatic stent was placed immediately before/after endoscopic retrograde cholangiography (ERC) or endoscopic sphincterotomy (EST). Conversely, in the LPSP group, a pancreatic stent was placed after partial/all completion of major endoscopic procedures. Results:From Nov. 2017 to May 2023, a total of 385 patients were divided into EPSP and 205 into LPSP. EPSP was associated with a decreased PEP occurrence compared to LPSP (2.9% vs. 7.3%; P=0.012). Similarly, hyperamylasemia was lower in the EPSP group (19.7% vs. 27.8%; P=0.026). Furthermore, sensitivity analysis using multivariable analysis and propensity score–matched (PSM) analysis also validated these findings. Conclusion:Early pancreatic stent placement reduced the incidence of PEP and hyperamylasemia compared to late pancreatic stent placement. Our findings favor pancreatic stenting immediately before/after ERC or EST.