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Background For large non-pedunculated rectal polyps, en bloc resection via endoscopic submucosal dissection (ESD) is typically recommended due to presumed higher risk of submucosal invasive cancer (SMIC) compared with the colon; however, data on cancer risk by location remain controversial.Objective Using the French ESD registry, we compared SMIC rates in large non-pedunculated colorectal polyps in the rectum versus colon. Procedural outcomes were also compared.Design From September 2019 to September 2022, all large non-pedunculated polyps resected by ESD in 13 centres were included. Oncological and procedural outcomes were analysed using propensity score matching (PSM) and inverse probability weighting, accounting for relevant influencing factors. A subgroup analysis was performed on cases from the three largest centres, where such polyps were exclusively treated with ESD.Results Among 3770 lesions, 3310 were analysed. Rectal lesions were larger (56.0 (40; 75) mm vs 47.0 (37; 62) mm), more often granular (80.0% vs 59.4%) and mixed nodular (54.0% vs 32.5%) (p<0.001). After PSM, submucosal cancer rates were not significantly different between rectal and colonic lesions of similar size and morphology (9.8% vs 8.9%, p=0.52). En bloc (97.7% vs 97.3%, p=0.757) and R0 resection rates (89.7% vs 89.5%, p=0.937) were also comparable. Perforation (5.5% vs 7.9%, p=0.057) and surgery for complications (0.1% vs 1.1%, p=0.051) showed a non-significant trend towards higher rates in colonic procedures. Subgroup analysis from the three centres exclusively performing ESD for large non-pedunculated polyps confirmed these findings.Conclusion In our multicentre registry, large non-pedunculated polyps do not show a higher prevalence of SMIC in the rectum compared with colon, when adjusted for relevant factors such as size and morphology. Therefore, risk features, rather than location, should guide the choice of resection technique. Technical outcomes were comparable between rectal and colonic ESD, with a trend for higher complication rates in the colon.Trial registration number NCT04592003.