Mucosa-associated lymphoid tissue (MALT) lymphoma of the papilla of Vater is rare, and little is known of either its association with Helicobacter pylori infection or the optimal treatment modalities. We describe the first case of MALT lymphoma involving the major papilla that remained unchanged despite eradication of H. pylori, but which regressed following radiotherapy. A 46-year-old asymptomatic man was admitted to hospital for treatment of MALT lymphoma involving the papilla of Vater. Duodenal endoscopy showed multiple granules around the major ampulla, and biopsies revealed mucosal proliferation of centrocyte-like cells, lymphoepithelial lesions, hyperplastic lymphoid follicles and plasmacytic differentiation. The lymphoma cells were positive for B-cell but negative for T-cell markers, and expressed Bcl-2 but showed no immunoreactivity for CD5, CD10 and cyclin D, consistent with MALT lymphoma. The patient was successfully treated with triple therapy of lansoprazole, amoxicillin and clarithromycin for 1 week for coexisting H. pylori infection in the stomach, but the lymphoma lesions remained unchanged. Then, involved-field irradiation was applied at a total dose of 30 Gy delivered in 1.5 Gy fractions without any adverse events. Six months later, repeat endoscopy revealed disappearance of the granular lesions and lack of lymphoma cells in biopsy specimens. Four years after the commencement of radiotherapy, the patient is still in complete remission. Radiotherapy seems a safe and effective treatment modality for low-grade MALT lymphoma of the ampulla of Vater.