IMPORTANCE: This is the largest series to date comparing end-to-side biliary reconstruction for all indications performed using either the duodenum or jejunum and with at least 2-year follow-up. OBJECTIVE: To demonstrate that duodenal anastomoses for biliary reconstruction are at least as safe and effective as Roux-en-Y jejunal anastomoses, with the benefits of operative simplicity and ease of postoperative endoscopic evaluation. DESIGN, SETTING, AND PARTICIPANTS: Retrospective record review with telephone survey of patients undergoing nonpalliative biliary reconstruction in the hepatopancreatobiliary surgery division of a high-volume tertiary care facility. INTERVENTIONS: Biliary reconstruction via either end-to-side Roux-en-Y jejunal anastomosis or direct duodenal anastomosis. MAIN OUTCOMES AND MEASURES: The primary end points were anastomosis-related complications (leak, cholangitis, bile gastritis, or stricture), and the secondary end points were overall complications, endoscopic or radiologic interventions, readmissions, and death. RESULTS: Ninety-six nonpalliative biliary reconstructions were performed between February 1, 2000, and November 23, 2011 for bile duct injury, cholangiocarcinoma, choledochal cysts, or benign strictures; the procedures included 59 duodenal reconstructions and 37 Roux-en-Y jejunal reconstructions. The groups were similar with regard to demographics, operative indications, postoperative length of stay, and mortality rates. However, anastomosis-related complications (leaks, cholangitis, or strictures) were fewer in the duodenal than the jejunal cohort (7 patients [12%] vs 13 [35%]; P = .009). Of patients with stricture, 5 of 9 in the jejunal cohort required percutaneous transhepatic access for management compared with only 1 of 2 in the duodenal cohort. CONCLUSIONS AND RELEVANCE: Duodenal anastomosis is a safe, simple, and often preferable method for biliary reconstruction. This anastomosis can successfully be performed to all levels of the biliary tree with low rates of leak, stricture, cholangitis, and bile gastritis. When anastomotic complications do occur, there is less need for transhepatic intervention because of easier endoscopic access.