Aim: Ampullary adenomas have the potential to progress from benign to malignant lesions. Endoscopic ampullectomy as curative therapy has gained credibility as a safe and effective alternative to surgical resection. This study was designed to assess outcomes of endoscopic resection of ampullary neoplasms at a single center. Methods: Between May 1996 and August 2009, all patients referred to our center for endoscopic resection of an ampullary lesion were retrospectively identified. Patients were followed for complications and endoscopic surveillance performed per protocol to assess for recurrence. Results: Endoscopic ampullectomy for adenoma was performed in 38 patients (22 females; mean age, 54.3 years, range, 22-85 years), with high-grade dysplasia (HGD) diagnosed in 6 and low-grade dysplasia (LGD) in 32. A direct relationship was observed between HGD and tumor size (P = 0.03). Lesions less than 2.5 cm in size demonstrated no evidence of invasion. Mean follow-up duration was 17.2 ± 2 months (range, 0-82.5 months). Complications were uniformly mild and occurred in 6 (16%) patients: bleeding in 2, pancreatitis in 3, and infection in 1. Adenoma recurrence was documented in 6 (16%) patients, 4 with LGD and 2 with HGD; no patients had tumors that progressed from LGD to HGD or HGD to cancer. Kaplan-Meier analysis showed insignificant differences in recurrence between HGD and LGD groups (P = 0.13). Conclusions: Endoscopic ampullectomy is a safe and effective treatment for benign ampullary neoplasms and should become the treatment of choice rather than surgical therapy. © 2011 Springer Science+Business Media, LLC.