Attempts have been made to design optimal strategies for the immunotherapy of established tumors. In mice bearing pulmonary metastases from sarcomas, a substantial therapeutic synergy was seen when both interleukin-2 (IL-2) and alfa interferon (alpha-IFN) were administered compared with the effect of either agent given alone. This synergy was dependent on Lyt-2+ T cells, since therapeutic effects were abrogated in Lyt-2-depleted mice. The alpha-IFN and IL-2 combination was also synergistic with tumor-infiltrating lymphocytes in mediating the reduction of established lung metastases. These experiments demonstrate that combination immunotherapy can result in substantial reduction of established metastatic deposits and provide a rationale for the application of this treatment to patients with advanced cancer.