We show, in a series of established experimental breast adenocarcinomas and fibrosarcomas induced by carcinogen de novo in mice, that the therapeutic efficacy of doxorubicin treatment is dependent on CD8 T cells and IFN-γ production. Doxorubicin treatment enhances tumor antigen–specific proliferation of CD8 T cells in tumor-draining lymph nodes and promotes tumor infiltration of activated, IFN-γ–producing CD8 T cells. Optimal doxorubicin treatment outcome also requires both interleukin (IL)-1β and IL-17 cytokines, as blockade of IL-1β/IL-1R or IL-17A/IL-17Rα signaling abrogated the therapeutic effect. IL-23p19 had no observed role. The presence of γδ T cells, but not Jα18⁺ natural killer T cells, at the time of doxorubicin treatment was also important. In tumor samples taken from breast cancer patients prior to treatment with anthracycline chemotherapy, a correlation between CD8α, CD8β, and IFN-γ gene expression levels and clinical response was observed, supporting their role in the therapeutic efficacy of anthracyclines in humans. Overall, these data strongly support the pivotal contribution of both innate and adaptive immunity in treatment outcomes of anthracycline chemotherapy. Cancer Res; 71(14); 4809–20. ©2011 AACR.