Objective To investigate the clinical efficacy and safety of endoscopic submucosal dissection (ESD) for colorectal high-grade intraepithelial neoplasia (HGIN). Methods Data of 29 patients diagnosed as colorectal HGIN and underwent endoscopic submucosal dissection (ESD) from January 2016 to June 2019 were retrospectively analyzed. Postoperative pathology, total en bloc resection rate, curative resection rate, complication and follow-up results were recorded. Results The mean diameter of the lesions was (2.28±0.76) cm. A total of 53 cases were successfully treated by ESD, 3 cases were changed using endoscopy piecemeal mucosal resection, the en bloc resection rate was 94.64% (53/56). Postoperative diagnosis confirmed 52 cases of HGIN, 2 cases of HGIN with intra-mucosal cancers and 2 case of invasive cancer,the overall consistency rate between preoperative biopsies and postoperative pathological diagnosis was 92.86% (52/56), the curative resection rate was 96.43% (54/56). The incidence of intro-operative bleeding and postoperative delayed bleeding was 89.29% (50/56) and 3.57% (2/56) respectively. The incidence of intro-operative perforation was 5.36% (3/56) and no delayed perforation occurred. The median follow-up period was 17 months and one case recurred. Conclusion ESD is a safe and effective treatment for colorectal HGIN, but invasive cancer must be cautioned. ESD has high risk of intro-operative bleeding and perforation, therefore, the surgeon must have skilled operation and treatment experience for complications.