PURPOSE: Numerous immune-based strategies are currently being evaluated for cancer therapy in preclinical models and clinical trials. Whereas many strategies look promising in preclinical models, they are often evaluated before or shortly following tumor implantation. The elimination of well-established tumors often proves elusive. Here we show that a multimodal immune-based therapy can be successfully employed to eliminate established tumors. EXPERIMENTAL DESIGN: This therapy consists of vaccines directed against a self-tumor-associated antigen, the use of external beam radiation of tumors to up-regulate Fas on tumor cells, and the use of a monoclonal antibody (mAb) to reduce levels of CD4+CD25+ suppressor cells. RESULTS: We show here for the first time that (a) antigen-specific immune responses induced by vaccines were optimally augmented when anti-CD25 mAb was given at the same time as vaccination; (b) anti-CD25 mAb administration in combination with vaccines equally augmented T-cell immune responses specific for a self-antigen as well as those specific for a non-self antigen; (c) whereas the combined use of vaccines and anti-CD25 mAb enhanced antigen-specific immune responses, it was not sufficient to eliminate established tumors; (d) the addition of external beam radiation of tumors to the vaccine/anti-CD25 mAb regimen was required for the elimination of established tumors; and (e) T cells from mice receiving the combination therapy showed significantly higher T-cell responses specific not only for the antigen in the vaccine but also for additional tumor-derived antigens (p53 and gp70). CONCLUSIONS: These studies reported here support the rationale for clinical trials employing multimodal immune-based therapies.