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Periampullary diverticulum (PAD) is frequently encountered in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to investigate the association of PAD with pancreaticobiliary diseases as well as the impact of PAD on the technical success of ERCP and different methods of bile duct stone extraction.A total of 1489 cases of patients with PAD were identified from 6390 patients who underwent ERCP. These patients were compared with 1500 controls without PAD in terms of biliary stone formation, technical success, and complications of ERCP.Patients with PAD had increased prevalence of bile duct stones, gallstones, and cholangitis (P<0.01). Successful cannulation rates were similar in the PAD and the control group (98.59 vs. 99.07%, P=0.225). The incidence of complications did not differ between the PAD and the control group. Successful stone removal rate of endoscopic sphincterotomy (EST) was lower in the PAD group than in the control group (83.53 vs. 94.31%, P=0.005). In patients with PAD, the rate of successful stone removal was lower in the EST group than in the endoscopic papillary balloon dilation (EPBD) and EPBD combined with limited EST (ESBD) group. The rates of complications were similar among different treatments (EST, EPBD, or ESBD) in patients with PAD.PAD is associated with bile duct stones, gallstones, and cholangitis. In addition, PAD should not be considered a barrier to a successful cannulation. Moreover, EST is less effective than EPBD and ESBD in patients with PAD, whereas EST, EPBD, and ESBD are equally safe in patients with PAD.