Introduction: Endoscopic submucosal resection (ESD) is well established as a curable and safety procedure even for large superficial neoplasias of the stomach, esophagus and colon. However, duodenal ESD is technically challenging because of anatomical specificities and has not been accepted as a standard method of local resection to date. This study aimed to validate the feasibility and long-term outcomes of ESD applied to superficial nonampullary duodenal tumors (SNADT), larger than 20 mm, which are outside the indication for conventional EMR. Methods: 59 patients, with 59 large SNADTs, who underwent ESD between April 2005 to June 2016 were included in the study. The short- and long-term outcomes were retrospectively evaluated, related to tumor size, resection size, histological type, invasion depth, complete resection rate, operation time, perforation rate, delayed bleeding rate, local recurrence rate, distant metastasis, and survival rate. Results: The median sizes of tumors and resected specimens were, respectively, 25mm (range 20-70mm) and 35.0mm (range 22- 80mm). Histopathological findings showed 25 adenocarcinomas (23 mucosal, 2submucosal) and 34 adenomas (25 high grade dysplasia, 9 low grade dysplasia). The complete resection rate was 86.4% (51/59 tumors). The mean operation time was 153.3minutes. Perforation during ESD occurred in 13.6% (8/59) and delayed bleeding occurred in 10.2% (6/59). Among the cases with prophylactic closure of the mucosal defect, the delayed bleeding rate was decreased to 3.8% (1/26). Delayed perforation occurred the next day in 1 ESD patient without prophylactic closure, who required local closure and drainage of an abscess by open surgery 5 days after ESD. The median observation period was 59.7 months (range 0.7-131.1months), and no local recurrence or distant metastasis was seen during this time, representing a disease-free survival rate of 100%. Conclusion: ESD for large SNADT is feasible with favorable long-term outcomes. However, because of the high complication rate due to its technical difficulty, experience and skill of the operator are essential. And the prophylactic endoscopic closure of mucosal defects after ESD could prevent hazardous delayed complications.