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Endoscopic removal of large, nonpedunculated colorectal lesions is challenging. Long-term outcome data based on standardized protocols, including detailed inspection of the resection site, are scarce. The aims of the present study were to evaluate the safety and efficacy of endoscopic resection (ER) of large, nonpedunculated lesions (LNLs; >20 mm) and to assess the long-term recurrence rate afterward.A total of 243 consecutive patients (141 men, 102 women) with 252 adenomas (>20 mm) was followed up using a standardized protocol after complete ER. After endoscopic treatment, the patients received standardized follow-up examinations after 3–6 months and 12 months. The postpolypectomy scar was re-examined, assessed for residual neoplasia, and biopsied at each follow-up colonoscopy.Evident residual neoplasia was noted after 3–6 months in 58 of 183 lesions (31.69%). After 12 months, 126 LNLs were examined, with 19 late recurrences (16.37%). Twenty-one (6.5%) postpolypectomy scars were not detected during 321 surveillance examinations. Biopsy evidence of residual/recurrent lesions was found in 16 of 228 macroscopically inconspicuous polypectomy scars (7%). All residual adenomas were treated using ER and/or argon plasma coagulation. There were 43 complications with the 252 lesions (17%), including 20 major complications (7.9%), all managed conservatively.A detailed study design with systematic biopsies of inconspicuous scars reveals a significant number of residual adenomas after completed resection. However, these residual neoplasias can be effectively treated at follow-up colonoscopies.