Objective: To compare the clinical benefits of classic endoscopic submucosal dissection (ESD) and hybrid ESD for the treatment of colorectal epithelium-derived tumors. Methods: The current investigation was a retrospective multicenter study of 418 patients who underwent ESD between January 2015 and April 2021 at Beijing Jishuitan Hospital. The patients were assigned to one of two groups based on the surgical procedure they underwent; a classic ESD group or a hybrid ESD group. The primary outcome was the rate of en bloc resection and complete resection. SPSS 26.0 was used for statistical analysis. Homogeneity of variance was assessed via Cochran's test. Normally distributed data with homogeneity of variance were analyzed via the t-test for independent samples. Non-normally distributed data and data with unequal variance were analyzed via the Kruskal-Wallis non-parametric test. Categorical data were analyzed via the Chi-square test or Fisher's exact test. Multivariable assessment was performed via logistic regression analysis. Results: The en bloc resection rates [89.4% (84/94) vs. 87.0% (194/223), χ2=0.34, P=0.558] and complete resection rates [85.1% (80/94) vs. 82.1% (183/223), χ2=0.33, P=0.510] were similar. Compared with classic ESD, procedures were shorter in the hybrid ESD group [22(7, 213) vs. 47(12, 680) min, Z=0.23, P<0.001], dissection was completed more rapidly [0.14(0.02, 0.32) vs. 0.10(0.02, 0.41) cm2/min, Z=0.08, P<0.001], and there was a higher rate of perforation (9.6% vs. 2.2%, χ2=2.67, P=0.006). Laterally spreading tumor granular type nodular mixed, non-granular type pseudo-depressed, flat-elevated type (odds ratio 2.826, P=0.012), and tumor location (odds ratio 6.970, P=0.005) were independently associated with complete resection in the hybrid ESD group. Conclusion: Classic ESD and hybrid ESD had similar en bloc and complete resection rates for colorectal epithelium-derived tumors, but hybrid ESD had shorter operation times. With respect to hybrid ESD, factors associated with failure of complete resection included lesion type and crossing tissue boundaries.