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The use of needle-knife fistulotomy technique in patient with periampullary diverticula (PAD) for biliary duct cannulation may lead to risk of complications. The present study aimed to investigate the association between PAD and the complications of endoscopic retrograde cholangiopancreatography (ERCP), unsuccessful cannulation rates and to determine the rates of cannulation complications using sphincterotomy and needle-knife fistulotomy.The ERCP procedures were held in Gastroenterology Endoscopy Unit between September 2015 and October 2016 and were retrospectively evaluated. The patients were divided into two groups, a PAD group and a non-PAD group. These groups were compared regarding demographic characteristics, ERCP complications and mortality.A total of 827 patients fulfilling the criteria for ERCP were enrolled in the study. Of 827 patients, 164 had PAD and 663 did not have PAD (non-PAD). The success rate of cannulation was 98.8% in patients with PAD and 98.6% in patients without PAD. There was no statistical difference of cannulation types with sphincterotomy and with needle-knife fistulotomy between the two groups. Mean baseline number of guide wire cannulation attempts was 1.96±0.20 in PAD group. No complications were observed in PAD patients treated with needle-knife fistulotomy. ERCP-related complications rates (bleeding, pancreatitis, and perforation) were higher in the PAD group (P=0.007).In conclusion, there is a strong association between PAD and higher rates of cannulation complications, independent of cannulation technique. In certain situations, and in the hands of experienced endoscopists, needle-knife fistulotomy might be a feasible option for successful biliary cannulation in certain patients with PAD.