Introduction: Aim of our observational and retrospective study is to compare efficacy and indications of endoscopic full-thickness resection device (FTRD) with the over-the-scope (OVESCO) clip closure for en bloc resection of colorectal lesions (including adenomas, early carcinomas, inflammatory polyps and neuroendocrine tumors)., Material and Methods: This article collected 36 cases of colorectal neoplasms from a single Italian referral center per colorectal disease treatment. Primary endpoints included en bloc resection, R0 resection and an early discharge of the patient. Secondary endpoints included procedure-related adverse events., Results: Mean procedure time± standard deviation (SD) was 19.6±22.1 minutes and mean hospital stay (± SD) was 2.2±1.1 days. Overall, an en bloc resection was achieved in 34 cases (94.4%), with an R0 resection rate of 91.6%. Among the three not R0 patients, further additional treatments were needed., Discussion: Along the same line of other already published articles, the main current indications of EFTR by FTRD-OVESCO are limited to superficial or low-risk malignancy lesions (eg, adenomas, early cancers or subepithelial tumors), not suitable to conventional endoscopic resection or in patients with a severe surgical risk. Both en bloc resection rate and complication rate are aligned with other authors' data., Conclusions: EFTR by FTRD system represents an effective and safe options whenever a recurrent lesion in a challenging environment occurres (eg, recent scar, low rectum or beyond a large colonic bend). Procedure-related adverse events are potentially severe, so that this novel technique should be performed by "expert hands"., Key Words: Difficult polypectomies, Early carcinomas, Endoscopic Full-Thickness Resection (EFTR), Full-Thickness Resection Device (FTRD) by Over-The-Scope (OVESCO) clip closure, Literature overview, Single center experience.