A case of poorly differentiated adenocarcinoma of the small bowel with extensive lymph node metastases is herein presented, which responded to methotrexate/5-fluorouracil (MTX/5-FU) sequential therapy. The lymph node metastases disappeared completely after 10 months of treatment. After recurrence, combination therapy with radiation, hyperthermia, and cisplatinum were also effective in reducing the degree of nodal swelling while still allowing the patient to maintain her accustomed lifestyle for a prolonged period of time. Further multi-institutional studies are still needed, however, to fully assess this new therapeutic regimen for small bowel cancers.