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Background Biliary self-expanding metal stents (SEMS) are commonly placed during endoscopic retrograde cholangiopancreatography for the management of biliary obstruction. However, it is unclear whether SEMS placement is associated with an increased risk of post-ERCP pancreatitis (PEP). We evaluated the association between biliary SEMS placement and PEP using a large prospective multicenter ERCP registry.Methods We used prospectively collected data from patients enrolled in the Calgary Registry for Advanced and Therapeutic Endoscopy (CReATE). Adult patients undergoing ERCP for biliary indications were included. The primary exposure was placement of a biliary SEMS. The primary outcome was PEP. Multivariable logistic regression was performed with the inclusion of patient and procedural factors known to be associated with PEP as covariates with effect estimates presented as odds ratios (OR) with 95% confidence intervals (CI).Results Among 11,729 included ERCPs, of which 1,450 (12.4%) involved SEMS placement. Overall, PEP occurred in 440 patients (3.8%). The crude incidence of PEP was significantly higher in the SEMS group compared with controls (6.97% vs 3.3%, p<0.001). On multivariable analysis, SEMS placement was independently associated with increased odds of PEP (OR 2.41, 95% CI 1.89–3.05, p<0.001). Other independent predictors included female sex (OR 1.35, 95% CI 1.11–1.65), greater than five common bile duct cannulation attempts (OR 1.93, 95% CI 1.55–2.42), pancreatic duct cannulation (OR 2.90, 95% CI 2.28–3.68), bile duct cannulation time >5 minutes (OR 1.39, 95% CI 1.11–1.74), and biliary sphincterotomy (OR 1.27, 95% CI 1.02–1.59). Pancreatic duct stent placement was protective (OR 0.59, 95% CI 0.43–0.79).Conclusions In this large registry-based cohort, biliary SEMS placement was independently associated with higher odds of post ERCP pancreatitis. These findings can inform risk stratification, utilization of prophylactic measures, and procedural planning.