Large flat colorectal polyps are often encountered during screening colonoscopies. The most frequently used approach for resecting these polyps is endoscopic mucosal resection, which is associated with a substantial rate of recurrent or residual adenoma, necessitating routine follow-up colonoscopy within months. An alternative endoscopic resection technique, endoscopic submucosal dissection, may enable en bloc resection of such polyps, potentially reducing the rate of recurrent or residual adenoma. This randomized controlled trial compared these 2 endoscopic resection techniques in terms of the rate of neoplastic local recurrence during the 6-month follow-up colonoscopy. Visual Abstract. Endoscopic En Bloc Versus Piecemeal Resection of Large Nonpedunculated Colonic Adenomas: Large flat colorectal polyps are often encountered during screening colonoscopies. The most frequently used approach for resecting these polyps is endoscopic mucosal resection, which is associated with a substantial rate of recurrent or residual adenoma, necessitating routine follow-up colonoscopy within months. An alternative endoscopic resection technique, endoscopic submucosal dissection, may enable en bloc resection of such polyps, potentially reducing the rate of recurrent or residual adenoma. This randomized controlled trial compared these 2 endoscopic resection techniques in terms of the rate of neoplastic local recurrence during the 6-month follow-up colonoscopy. Background: Endoscopic resection of adenomas prevents colorectal cancer, but the optimal technique for larger lesions is controversial. Piecemeal endoscopic mucosal resection (EMR) has a low adverse event (AE) rate but a variable recurrence rate necessitating early follow-up. Endoscopic submucosal dissection (ESD) can reduce recurrence but may increase AEs. Objective: To compare ESD and EMR for large colonic adenomas. Design: Participant-masked, parallel-group, superiority, randomized controlled trial. (ClinicalTrials.gov: NCT03962868) Setting: Multicenter study involving 6 French referral centers from November 2019 to February 2021. Participants: Patients with large (≥25 mm) benign colonic lesions referred for resection. Intervention: The patients were randomly assigned by computer 1:1 (stratification by lesion location and center) to ESD or EMR. Measurements: The primary end point was 6-month local recurrence (neoplastic tissue on endoscopic assessment and scar biopsy). The secondary end points were technical failure, en bloc R0 resection, and cumulative AEs. Results: In total, 360 patients were randomly assigned to ESD (n = 178) or EMR (n = 182). In the primary analysis set (n = 318 lesions in 318 patients), recurrence occurred after 1 of 161 ESDs (0.6%) and 8 of 157 EMRs (5.1%) (relative risk, 0.12 [95% CI, 0.01 to 0.96]). No recurrence occurred in R0-resected cases (90%) after ESD. The AEs occurred more often after ESD than EMR (35.6% vs. 24.5%, respectively; relative risk, 1.4 [CI, 1.0 to 2.0]). Limitation: Procedures were performed under general anesthesia during hospitalization in accordance with the French health system. Conclusion: Compared with EMR, ESD reduces the 6-month recurrence rate, obviating the need for systematic early follow-up colonoscopy at the cost of more AEs. Primary Funding Source: French Ministry of Health. [ABSTRACT FROM AUTHOR]