Targeted interleukin-2 (IL-2) therapy with immunocytokines (i.e. antibody-cytokine fusion proteins) is effective in eradicating established hepatic and pulmonary metastases of melanoma in animal model systems. The effector mechanisms responsible for this antitumor effect in syngeneic, immunocompetent mice involves mainly CD8+ T cells. This was clearly indicated by immunohistochemical analyses, in vivo depletion studies and cytotoxicity tests. Such CD8+ T cells, isolated from tumor-bearing mice after immunocytokine therapy, exerted a major histocompatibility complex class I-restricted cytotoxicity against the same tumor in vitro. Because of this cellular immune response, antibody-directed IL-2 therapy can even address established metastases displaying extensive heterogeneity in the expression of the targeted antigen. The effector mechanisms induced by immunocytokines facilitate partial regressions of large subcutaneous melanoma exceeding more than 5% of the body weight. These results demonstrate the ability of immunocytokines to induce a T-cell-dependent host immune response capable of eradicating established melanoma metastases in clinically relevant organs and offers an effective, new tool for immunotherapy of malignant melanoma.