Objective To evaluate the clinical efficacy of small endoscopic sphincterotomy combined large-bal-loon dilation in treatment of common bile duct stones 1.0~2.5 cm in diameter. Methods 426 patients with large common bile duct (CBD) stones 1.0~2.5 cm in size were reviewed in our hospital between June 2010 and June 2014. They were randomized underwent small endoscopic sphincterotomy combined large-balloon dilation (SESPLBD) (n=218) or endoscopic sphincterotomy (EST) ( n= 208) for lithotripsy. The therapeutic outcome and complications were reviewed and compared. Results SESPLBD had higher complete duct clearance in one session (95.41 % vs. 93.75%), but there was no statistical significant difference. Bleeding was much less occurred in SESPLBD than in EST (2.29 % vs. 7.69 %, P= 0.025), especially when the stones were bigger than 1.5 cm in diameter. Mechanical lithotripsy was performed less in SESPLBD (13.76%vs 25.96 %, P=0.002), especially when the stones were 1.5 ~2.0 cm in diameter. There was no statistical significant difference in the incidence rate of post-ERCP pancreatitis (9.17 % vs. 6.73 %,P = 0.452), hyperamylasemia (19.72 % vs. 18.27 %,P = 0.796), perforation and death. Conclusions SESPLBD could be a safe method for large bile duct stones 1.0~2.5 cm in size. Compared with routine EST, it had less bleeding rate and mechanical lithotripsy requirement without increasing the incidence rate of post-ERCP pancreatitis or hyperamylasemia.