Question What technique is best for surgical management of gallstone disease with biliary duct calculi? Findings In this systematic review and network meta-analysis of 20 randomized clinical trials that included 2489 unique patients and 4 surgical techniques combining laparoscopic cholecystectomy with a second technique, the rendezvous approach (laparoscopic cholecystectomy plus intraoperative cholangiopancreatography) was associated with the highest rates of safety and success compared with the other approaches. Meaning The rendezvous approach should be the first choice for patients with gallstone disease and biliary duct calculi. Importance Several techniques are used for surgical treatment of gallstone disease with biliary duct calculi, but the safety and efficacy of these approaches have not been compared. Objectives To compare the efficacy and safety of 4 surgical approaches to gallstone disease with biliary duct calculi. Data Sources MEDLINE, Scopus, and ISI-Web of Science databases, articles published between 1950 and 2017 and searched from August 12, 2017, to September 14, 2017. Search terms used were LCBDE , LC , preoperative , ERCP , postoperative , period , cholangiopancreatography , endoscopic , retrograde , rendezvous , intraoperative , one-stage , two-stage , single-stage , gallstone , gallstones , calculi , stone , therapy , treatment , therapeutics , surgery , surgical , procedures , clinical trials as topic, random , and allocation in several logical combinations. Study Selection Randomized clinical trials comparing at least 2 of the following strategies: preoperative endoscopic retrograde cholangiopancreatography (PreERCP) plus laparoscopic cholecystectomy (LC); LC with laparoscopic common bile duct exploration (LCDBE); LC plus intraoperative endoscopic retrograde cholangiopancreatography (IntraERCP); and LC plus postoperative ERCP (PostERCP). Data Extraction and Synthesis A frequentist random-effects network meta-analysis was performed. The surface under the cumulative ranking curve (SUCRA) was used to show the probability that each approach would be the best for each outcome. Main Outcomes and Measures Primary outcomes were the safety to efficacy ratio using overall mortality and morbidity rates as the main indicators of safety and the success rate as an indicator of efficacy. Secondary outcomes were acute pancreatitis, biliary leak, overall bleeding, operative time, length of hospital stay, total cost, and readmission rate. Results The 20 trials comprised 2489 patients (and 2489 procedures). Laparoscopic cholecystectomy plus IntraERCP had the highest probability of being the most successful (SUCRA, 87.2%) and safest (SUCRA, 69.7%) with respect to morbidity. All approaches had similar results regarding overall mortality. Laparoscopic cholecystectomy plus LCBDE was the most successful for avoiding overall bleeding (SUCRA, 83.3%) and for the shortest operative time (SUCRA, 90.2%) and least total cost (SUCRA, 98.9%). Laparoscopic cholecystectomy plus IntraERCP was the best approach for length of hospital stay (SUCRA, 92.7%). Inconsistency was found in operative time (indirect estimate, 19.05; 95% CI, 2.44-35.66; P = .02) and total cost (indirect estimate, 17.06; 95% CI, 3.56-107.21; P = .04). Heterogeneity was observed for success rate (τ, 0.8), operative time (τ, >1), length of stay (τ, >1), and total cost (τ, >1). Conclusions and Relevance The combined LC and IntraERCP approach had the greatest odds to be the safest and appears to be the most successful. Laparoscopic cholecystectomy plus LBCDE appears to reduce the risk of acute pancreatitis but may be associated with a higher risk of biliary leak. This systematic review and meta-analysis compares 4 surgical strategies that combine laparoscopic cholecystectomy and a second technique to assess which strategy is most successful in patients with gallstone disease with common bile duct stones.