Background and Aims: Endoscopic full-thickness resection (eFTR) is emerging as a minimally invasive alternative to surgery for complex colorectal lesions. Previous studies have demonstrated favorable safety results; however, large studies representing a generalizable estimation of adverse events (AEs) are lacking. Our aim was to provide further insight in AEs after eFTR. Methods: Data from all registered eFTR procedures in the German and Dutch colorectal full-thickness resection device registries between July 2015 and March 2021 were collected. Safety outcomes included immediate and late AEs. Results: Of 1892 procedures, the overall AE rate was 11.3% (213/1892). No AE-related mortality occurred. Perforations occurred in 2.5% (47/1892) of all AEs, 57.4% (27/47) of immediate AEs, and 42.6% (20/47) of delayed AEs. Successful endoscopic closure was achieved in 29.8% of cases (13 immediate and 1 delayed), and antibiotic treatment was sufficient in 4.3% (2 delayed). The appendicitis rate for appendiceal lesions was 9.9% (13/131), and 46.2% (6/13) could be treated conservatively. The severe AE rate requiring surgery was 2.2% (42/1892), including delayed perforations in .9% (17/1892) and immediate perforations in .7% (13/1892). Delayed perforations occurred between days 1 and 10 (median, 2) after eFTR, and 58.8% (10/17) were located on the left side. Other severe AEs were appendicitis (.4%, 7/1892), luminal stenosis (.1%, 2/1892), delayed bleeding (.1%, 1/1892), pain after eFTR close to the dentate line (.1%, 1/1892), and grasper entrapment in the clip (.1%, 1/1892). Conclusions: Colorectal eFTR is a safe procedure with a low risk for severe AEs in everyday practice and without AE-related mortality. These results further support the position of eFTR as an established minimally invasive technique for complex colorectal lesions.