Objective To explore the safety and effectiveness of endoscopic retrograde cholangiopancreatography （ERCP） for bile duct stones with periampullary diverticula （PAD）. Methods Data of 2，103 patients with common bile duct stones（CBD stones）， who underwent therapeutic ERCP for the first time from April 2013 to March 2016， were prospectively analyzed. Patients were divided into two groups according to presence or absence of PAD （PAD group and non-PAD group）. Success rate of ERCP， complete clearance rate of the CBD stones after the first attempt and difficult cannulation rate were compared between the two groups. Results The difficult CBD cannulation rate was 14.87％（117／787） in PAD group and 9.93％ （123／1 239） in non-PAD group with significant difference （P=0.001）. Successful CBD cannulation was achieved in 96.92％ （787／812） patients in PAD group and 95.97％ （1 239／1 291） in non-PAD group （P=0.156）. The complete clearance rate of CBD stones after the first attempt was 85.39％ （672／787） in PAD group and 87.09％ （1 079／1 239）in non-PAD group （P=0.154）. There was no significant difference between the two groups in the complication rate［26／812（3.20％） VS 33／1 291（2.56％）， P=0.833］. Conclusion Although PAD increases the difficulty of ERCP， ERCP is an effective and safe method for patients of CBD stones with PAD.