Antibody-based therapies for cancer rely on the expression of defined antigens on neoplastic cells. However, most tumors display heterogeneity in the expression of such antigens. We demonstrate here that antibody-targeted interleukin 2 delivery overcomes this problem by induction of a host immune response. Immunohistochemical analysis demonstrated that the antibody-interleukin 2 fusion protein-induced eradication of established tumors is mediated by host immune cells, particularly CD8+ T cells. Because of this cellular immune response, antibody-directed interleukin 2 therapy is capable to address established metastases displaying substantial heterogeneity in expression of the targeted antigen. This effector mechanism further enables the induction of partial regressions of large subcutaneous tumors that exceeded more than 5% of the body weight. These observations indicate that antibody-directed cytokine delivery offers an effective new tool for cancer therapy.