Introduction: An asymptomatic 54-year-old male referred for surveillance colonoscopy had biopsies from a thickened sigmoid fold, suggesting a mucosa-associated lymphoid tissue (MALT) lymphoma. Pathology showed atypical lymphocytic infiltrate involving mucosa and submucosa with intense CD20+ infiltrate. Colonoscopy 5 years earlier showed hyperplastic and adenomatous polyps. He denied constitutional symptoms, exposure to radiation, history of malignancy, and previous H. pylori infection. The physical exam did not show lymphadenopathy. CBC, lactate dehydrogenase, serum, or urine protein electrophoresis, and a CT of the chest, abdominal, and pelvis were normal. Endoscopic ultrasound showed a minimally thickened colonic mucosa, normal submucosa, muscularis mucosa, and no regional lymphoadenopathy. H. pylori stool antigen test was negative, but empiric antibiotic treatment was given. A colonoscopy was repeated in 1 year and showed a flat granular 2-cm lesion at 30 cm. Endomucosal resection and cautery of the resection edges were performed with tattooing of the site. Pathology from the polypectomy showed atypical lymphoid proliferation with CD20+ B cells arranged in a nodular and merging pattern, expanding beyond the lamina prioria. These findings were consistent with a MALT lymphoma. CD3 and CD5 showed a few clusters of T cells within the B cells. CD21 highlighted interconnected clusters of follicular dendritic cells. CD10 was negative. CD138 showed rare isolated plasma cells. The patient was referred to surgery for a successful laparoscopic sigmoid resection with negative margins. Colonic MALT lymphoma is a rare clinical entity, has an unknown etiopathogenesis, and may present asymptomatically. A reported association with H. pylori infection exists but is not present in the majority of cases. Antibiotic treatment, even without documentation of H. pylori infection, has been reported to resolve colonic MALT lymphomas. Our case demonstrated failure to eradicate colonic MALT lymphoma with empiric H. pylori antibiotic treatment. Review of the literature shows most cases are treated with complete endoscopic resection or surgical resection, although chemotherapy, radiation, and strict observation have also been used for treatment.