Methods: We retrospectively analysed all consecutive patients, in one center, that performed ESD for gastrointestinal lesions previously subjected to resection or ablation therapy, surgery or radiotherapy, using our prospectively collected database. Short and long-term outcomes were evaluated, as well as the safety of ESD in these patients. Results: From all ESD performed, 40 lesions (6.6%) had undergone previous manipulation (esophageal, n=3; gastric, n=5; colon, n= 4; rectal, n=28). Previous EMR was the most common cause of prior manipulation (65%, n=26), followed by surgery (15%, n=6), radiotherapy (5%, n= 2) and ESD (5%, n=2); 10% (n=4) had prior manipulation by more than one technique. Complete procedure was achieved in 97.5% of cases (n=39), with en bloc resection rate of 80% (n=32), and curative resection (R0) of 51.3% (n=20). For non-curative resected lesions, 68.4% (n=13) was a high local risk resection (piecemeal resection, n=7; HM1, n=6) and 31.6% (n=6) was high-risk resection. Three cases (50%) of high-risk resected lesions were submitted to surgery. Local recurrence was 5% (n=2), that were successfully retreated endoscopically. Complication rate was 12.5% (n=5) (bleeding 7.5%, n=3; perfuration 5%, n=2) all successfully treated during the procedure. Mean follow-up time was 842 ± 513 days (mean ± sd).Conclusions:These cases are typically associated with severe submucosal fibrosis leading to a lower rate of en blocand of curative resection. However, ESD was associated with a high efficacy treatment rate with a good safety profile, making this minimal invasive treatment first-line therapy in the management of these lesions.