Duodenal lymphoma accounts for a small percentage of gastrointestinal tumors and has a very poor prognosis. The majority of patients have little or no cure with limited time of remission. Median survival is 5 to 10 years, and most patients die of lymphoma, its complications, or complications of therapy. We report a patient with lymphoma refractory to treatment with cyclophosphamide, vincristine, and prednisone, who was successfully treated with rituximab, a CD-20 monoclonal antibody.