The adoptive transfer of tumor-infiltrating lymphocytes (TIL) expanded in interleukin-2 (IL-2) to mice bearing micrometastases from various types of tumors showed that TIL are 50 to 100 times more effective in their therapeutic potency than are lymphokine-activated killer (LAK) cells. Therefore the use of TIL was explored for the treatment of mice with large pulmonary and hepatic metastatic tumors that do not respond to LAK cell therapy. Although treatment of animals with TIL alone or cyclophosphamide alone had little impact, these two modalities together mediated the elimination of large metastatic cancer deposits in the liver and lung. The combination of TIL and cyclophosphamide was further potentiated by the simultaneous administration of IL-2. With the combination of cyclophosphamide, TIL, and IL-2, 100% of mice ( n = 12) bearing the MC-38 colon adenocarcinoma were cured of advanced hepatic metastases, and up to 50% of mice were cured of advanced pulmonary metastases. Techniques have been developed to isolate TIL from human tumors. These experiments provide a rationale for the use of TIL in the treatment of humans with advanced cancer.