Objective To assess the efficacy and safety of endoscopic piecemeal mucosal resection (EPMR) and endoscopic submucosal dissection (ESD) in the treatment of larger (≥10-15 mm) non-ampullary duodenal lesions. Methods The data of 21 patients with larger (≥10-15 mm) non-ampullary duodenal lesions, who underwent EPMR or ESD in Beijing Friendship Hospital from February 2013 to August 2018 were retrospectively analyzed. According to the treatment plan, the patients were divided into the EPMR group (n=13) and the ESD group (n=8). The operation time, pathological histological evaluation and complications of each group were summarized. Results In the EPMR group, all 13 lesions were originated from the mucosa. The diameter of the lesion estimated by endoscopy and the size of the resected specimen were 22±12 mm and 26±15 mm, respectively, the median operation time was 39.0 (23.0, 45.0) min, and 12 lesions were closed with metal clips. For pathological assessment, there were 2 cases of ectopia gastric mucosa, 7 cases of low grade intraepithelial neoplasia, and 4 cases of high grade intraepithelial neoplasia. And 5 cases were horizontal margin positive (low grade intraepithelial neoplasia) in the 13 lesions. Complications occurred in 2 patients, including 1 case of perioperative bacteremia, which was cured after anti-infective treatment, and another case of intraoperative perforation, which was recovered after emergency surgery. In the ESD group, there were 6 mucosal lesions and 2 submucosal lesions. The diameter of the lesion estimated by endoscopy and the size of the resected specimen were 17±5 mm and 20±7 mm, respectively, the median operation time was 47.5 (34.0, 68.0) min, and all 8 lesions were closed with metal clips. For pathological assessment, there were 3 cases of low grade intraepithelial neoplasia, 3 cases of high grade intraepithelial neoplasia, 1 case of submucosal cyst, and 1 case of lymphangioma. All 8 cases were horizontal margin negative, and low-grade intraepithelial neoplasia was suspected at the vertical margin of 1 case, which failed to achieve complete resection. Perioperative perforation occurred in 3 cases. One case recovered after endoscopic treatment, another case was unsatisfactory under endoscopy, and recovered after emergency surgery. The other case was recovered after laparoscopic treatment. Conclusion EPMR and ESD are both safe and effective for larger non-ampullary duodenal lesions, which is worthy of further clinical research.