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Background/Aims: Needle knife fistulotomy (NKF) is a technique to facilitate pancreatic and biliary duct access during ERCP. The double-guidewire technique (DGT) is also used in cases of difficult cannulation, but it can increase the incidence of post-ERCP-pancreatitis (PEP). This study examined the success and complication rates of NKF after unsuccessful standard cannulation or DGT in patients with pancreaticobiliary disease. Methods: The data of 209 patients who received NKF as a rescue procedure between January 2009 and December 2016 were reviewed retrospectively. The cannulation success and complication rates were assessed. Results: The overall cannulation success rate was 90.4%. The success rates of patients who received NKF after standard cannulation or DGT were similar (82.6% [142/172] and 73.0% [27/37], respectively, p=0.179). Furthermore, there was no significant difference in the incidence of procedure-related adverse events between the two groups (10.5% [18/172] and 16.2% [6/37], respectively, p=0.391). Endoscopic retrograde pancreatic drainage (ERPD) insertion decreased the incidence of PEP (0% [0/16] in ERPD and 14.6% [19/130] in non-ERPD, p=0.132) among patients who received PD cannulation. Conclusions: NKF is an effective and safe method that can be considered for rescue management after the initial failure of standard cannulation or DGT. NKF following standard cannulation can be preferred over NKF following DGT because of the higher success rate and the lower rate of pancreatitis, but the difference was not significant. PD stenting in patients at high risk of PEP can be considered to decrease pancreatitis.