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Double-guidewire cannulation (DGC) for selective biliary access has been associated with increased risk of post-ERCP pancreatitis (PEP) in patients who have had pancreatic duct (PD) contrast injection. The objective of this study was to determine whether DGC increases PEP risk in standard risk individuals when controlling for procedural aspects such as PD contrast injection.Consecutive adults with native papillae who underwent endoscopic retrograde cholangiopancreatography from 2009 to 2014 were retrospectively identified, and clinical data were collected.There were 879 subjects who met inclusion criteria. Increased incidence of PEP was observed after DGC (18% with DGC vs 4% without DGC, P < 0.005). Additional factors associated with increased PEP risk included the following: PD contrast injection, PD wire cannulations, and biliary stent placement. The association between DGC and increased PEP risk remained significant in a multivariate model controlling for age, sex, PD contrast injection, biliary sphincterotomy, biliary stent placement, and rectal indomethacin administration (odds ratio = 2.87, 95% confidence interval = 1.23–6.36).Double-guidewire cannulation is associated with increased risk of PEP when controlling for confounding variables. Prospective studies should be undertaken to assess whether prophylactic interventions reduce risk of PEP after DGC in an average-risk population.