We present two cases involving 50- and 75-year-old patients with large dysplastic lesions (40 mm and 50 mm) located in the second portion of the duodenum. Histology showed low-grade dysplasia with focal high-grade areas in the first case and predominant high-grade dysplasia in the second. Both lesions were situated near, but not involving, the ampulla of Vater, with a safety distance of more than 10 mm. En bloc resection was achieved using endoscopic submucosal dissection (ESD). Traction was applied in one case to clarify the cutting plane. The mucosal defects were successfully closed with a combination of the zipper-closure technique and the clip-and-string method. Both patients were discharged on postoperative day two. Follow-up endoscopy at three months showed no residual or recurrent lesions.