Approach to management of common bile duct stones (CBDS) by endoscopic retrograde cholangiopancreatography (ERCP) is not standardized. We examined outcomes by applying predetermined protocol for CBDS management. When standard extraction techniques failed at ERCP, presence of tapered bile duct and stone-duct ratio were calculated. Large balloon sphincteroplasty (LBS) and/or mechanical/single-operator cholangioscopy-guided lithotripsy was performed based on presence of tapered bile duct and stone-duct mismatch. Primary outcome was single-session ductal clearance. Secondary outcome was adverse events. Of 409 patients treated over 16 months, 321 (78.5%) had no tapered bile duct or stone-duct mismatch, and single-session ductal clearance was achieved using standard techniques in 99.7% over median duration of 14 min (interquartile range [IQR] 9-21 min). Of 88 (21.5%) patients with difficult CBDS, tapered duct was seen in 79 (89.8%) and/or stone-duct mismatch in 36 (40.9%). Single-session ductal clearance was achieved in all 88 patients (100%) by LBS in 79 (89.8%), mechanical lithotripsy in 20 (22.7%), and single-operator cholangioscopy-guided lithotripsy in 16 (18.2%) over a median duration of 29 min (IQR 17-47 min). Overall, single-session ductal clearance was achieved in 99.8% with adverse events in 17 (4.2%) that included perforation in two, postsphincterotomy bleeding in one, and mild/moderate post-ERCP pancreatitis in 14 patients. A predetermined protocol optimized outcomes by enabling single-session ductal clearance of CBDS with high technical success and low adverse events.