Background Endoscopic retrograde cholangiopancreatography (ERCP) is recommended by major guidelines for the removal of common bile duct (CBD) stones but is technically challenging in patients with low cardiopulmonary reserve and anatomic abnormalities of the upper gastrointestinal (GI) tract. Purpose To compare percutaneous transhepatic papillary balloon dilation (PTPBD) with ERCP for CBD stone removal. Materials and Methods Participants with one to three CBD stones (largest stone ≤30 mm) and without intrahepatic bile duct or gallbladder stones were eligible for this prospective cohort study. PTPBD was recommended in participants with low cardiopulmonary reserve or definitive anatomic abnormalities of the upper GI tract. Otherwise, both procedures were offered without preference. Follow-up, including abdominal CT, was conducted at 1-week and 1-, 3- and 6-month follow-up, and every 6 months thereafter. US and MR cholangiopancreatography were conducted if recurrence could not be confirmed with CT. Technical success rate was the primary outcome. Results A total of 531 participants were analyzed: there were 360 undergoing PTPBD (median age, 76 years; interquartile range [IQR], 64-82 years; 163 men) and 171 undergoing ERCP (median age, 66 years; IQR, 57-74 years; 94 men). The technical success rate was 99% (355 of 360) in the PTPBD group and 98% (167 of 171) in the ERCP group (relative risk, 1.02; P = .12). The incidence of overall complications was 4% (13 of 360) for PTPBD and 8% (13 of 171) for ERCP (relative risk, 0.27; 95% CI: 0.12, 0.61; P < .001). The PTPBD group showed a longer fluoroscopy time and a higher radiation exposure, with adjusted differences of 28.7 minutes (95% CI: 22.2, 35.2) and 384.3 mGy (95% CI: 296.5, 472), respectively. A propensity score-matching analysis (n = 123 per group) indicated that PTPBD had a slightly higher technical success rate and significantly fewer complications. Conclusion When compared with endoscopic retrograde cholangiopancreatography, percutaneous transhepatic papillary balloon dilation has a similar technical success rate and fewer perioperative complications but a higher radiation exposure. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by van Sonnenberg and Mueller in this issue.