Endoscopic submucosal dissection (ESD) effectively achieves en bloc resection of laterally spreading ampullary tumors, but significant recurrence remains a concern.

• Among 55 patients analyzed, the 3-year cumulative incidence of residual/recurrent tumors was 33%, with all recurrences confined to the papilla.
• Positive or indeterminate papillary ductal margins emerged as a leading risk factor, increasing the likelihood of recurrence by over eight times (HR 8.35).

Surgeons should approach ESD for ampullary lesions with caution, particularly regarding margin assessment to mitigate recurrence risks.