Although single-operator cholangioscopy (SOC)-guided lithotripsy and large balloon sphincteroplasty (LBS)-based techniques are effective rescue measures, the ideal approach to management of difficult bile duct stones is unclear. We conducted a randomized trial to compare the effectiveness of SOC-guided lithotripsy and LBS-based approaches for endoscopic management of difficult bile duct stones. Patients with difficult bile duct stones who failed retrieval using balloon or basket were randomly assigned to groups that received SOC-guided laser lithotripsy (SOC-LL, n= 33) or LBS (n= 33), from June 2016 through August 2018. When assigned treatment was unsuccessful, patients underwent mechanical lithotripsy before crossing over to the other group. The main outcome was treatment success, defined as ability to clear the duct in 1 session. Secondary outcomes were adverse events and treatment costs. A higher proportion of patients in the SOC-LL group had treatment success (93.9%) than in the LBS group (72.7%; P= .021). On multiple logistic regression analysis, treatment success was significantly associated with use of SOC-LL (odds ratio [OR], 8.7; 95% CI, 1.3-59.3; P= .026), stone to extrahepatic bile duct ratio of 1 or less (OR, 28.8; 95% CI, 1.2-687.6; P= .038), and lack of a tapered bile duct (OR, 26.9; 95% CI, 1.3-558.2; P= .034). There was no significant difference between groups in adverse events (9.1% in the SOC-LL group vs 3.0% in the LBS group, P= .61) or overall treatment cost ($16,684 in the SOC-LL group vs $10,626 in the LBS group; P= .097). In a randomized trial of patients with difficult bile stones that cannot be cleared by standard maneuvers, SOC-guided lithotripsy leads to duct clearance in a significantly higher proportion of patients than LBS-particularly when stone size exceeds the diameter of the extrahepatic bile duct. Adjunct lithotripsy might be required in patients with tapered distal bile duct, because LBS alone is less likely to be successful. ClinicalTrials.gov no: NCT00852072.