BACKGROUND: Submucosal tunneling endoscopic resection (STER) is considered an effective, safe and minimally invasive treatment for esophageal subepithelial lesions (SELs) with maximal dilameter less than 3.0 cm, yet its efficacy for lesions over 3.0 cm remains unclear. This study aimed to evaluate the application value of STER for SELs of varying sizes. METHODS: Consecutive patients with esophageal SELs who underwent STER were retrospectively enrolled from May 2017 to March 2024. Baseline characteristics, surgical information and prognosis were collected and compared among patients with SELs of different sizes, as defined by the maximal diameter of the postoperative specimen. RESULTS: A total of 133 patients were included, among whom 69 with SELs <
3.0 cm, 31 with SELs between 3.0 and 5.0 cm, 33 with SELs ≥ 5.0 cm. 1 case with SELs ≥ 5.0 cm was converted to endoscopic submucosal dissection (ESD) due to the tumor's adhesion to the epithelial layer. Among those who completed the STER procedure, the en bloc resection rate was 100.0% for all three subgroups, and the recurrence and metastasis rates were 0.0%, demonstrating that STER is effective for SELs of all sizes. However, SELs ≥ 5.0 cm were associated with more adverse events, a higher number of difficult procedures, and more frequent intensive care unit (ICU) transfers (all p <
0.050). CONCLUSIONS: STER is effective and safe for treating esophageal SELs. For lesions exceeding 5 cm, while still feasible, the procedure requires meticulous planning, advanced techniques and careful monitoring due to increased complexity and risks.