Abstract: Objective: To explore the effectiveness and safety of endoscopic submucosal dissection (ESD) in the treatment of ≥ 40 mm protruding colorectal tumors. Methods: Sixty-five patients with colorectal tumors who underwent surgical treatment in the Department of Anorectal Surgery of a hospital from July 2023 to June 2024 were selected and grouped according to the type of surgery, with 33 cases of endoscopic mucosal resection (EMR) patients included in the control group, and 32 cases of ESD patients included in the observation group. The surgical characteristics, adverse events, as well as the fasting time, postoperative hospital stay, and hospital costs of the two groups were compared. Results: The whole resection rate of the control group and the observation group was 100% and 69.70%, respectively, and the difference was statistically significant (P < 0.05); there was no incidence of intraoperative hemorrhage, delayed hemorrhage, and perforation adverse events in the observation group, and the intraoperative hemorrhage rate of the control group was9.09%, the delayed hemorrhage rate was 6.06%, and the perforation rate was 3.03%, and the difference was statistically significant (P < 0.05); postoperative fasting time in the control group and observation group was 1.13 ± 0.32 d vs 1.22 ± 0.33 d, postoperative hospital stay was 4.1 ± 1.3 d vs 4.6 ± 1.5 d, and total hospitalization cost was 9,639.8 ± 1,303.5 yuan vs 9,978.6 ± 1,506.8 yuan, with statistically significant differences (P > 0.05). Conclusion: The efficacy of endoscopic submucosal dissection for the treatment of ≥ 40 mm protruding colorectal tumors is precise, with a high rate of whole resection, which can significantly reduce the risk of intraoperative bleeding, delayed bleeding, perforation, and otheradverse events