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Background: Ampullary adenomas are rare and potentially malignant. Surgery was the standard treatment but endoscopic papillectomy (EP) is a possible alternative., Aim: We retrospectively evaluated the principal clinical outcomes of EP in all patients referred to our unit also dividing sporadic ampullary adenoma (SAA) from familial adenomatous polyposis (FAP)-associated adenomas., Methods: All consecutive patients who underwent endoscopic papillectomy because of ampullary adenoma were considered. The primary outcome was the technical success of EP. Secondary outcomes included the number of procedures, the adverse event rate, the recurrence rate, the concordance of histology pre- and post-EP, and the evaluation of factors related to technical success., Results: Between January 2001 and December 2015, sixty-two patients were included (21 FAP and 41 SAA). Technical success was achieved in 75.8% and was different in the two groups (FAP 95.2%, SAA 65.8%, p 0.025). Intraductal invasion was negatively associated with technical success (41.7% vs. 84.0%; p 0.005). The intestinal subtype was predictive of success (79.7% vs. 0%; p 0.012) as well as en bloc resection (90.3% vs. 61.3%; p 0.016). Adverse events were reported in 14 patients (22.6%)., Conclusions: EP is an effective and safe procedure and is a viable alternative to surgery., Trial Registration: ClinicalTrials.gov Identifier: NCT03494543.