Breast cancer is immunogenic and well suited to treatment via immunomodulation. The disease is often treated to remission and time to relapse is generally measured in years in many cases. Immune-based therapeutics, such as cancer vaccines, may be able to affect the clinical progression of micrometastatic disease. Immune targets must be identified that have the potential to inhibit tumor growth. Insulin-like growth factor-binding protein-2 (IGFBP-2) has direct effects on breast cancer proliferation via stimulation of critical signaling pathways. We questioned whether IGFBP-2 was an immune target in breast cancer. IGFBP-2-specific IgG antibody immunity was preferentially detected in breast cancer patients compared with controls (P = 0.0008). To evaluate for the presence of T-cell immunity, we identified potential pan-HLA-DR binding epitopes derived from IGFBP-2 and tested the peptides for immunogenicity. The majority of epitopes elicited peptide-specific T cells in both patients and controls and had high sequence homology to bacterial pathogens. IGFBP-2 peptide-specific T cells could respond to naturally processed and presented IGFBP-2 protein, indicating that these peptides were native epitopes of IGFBP-2. Finally, both immunization with IGFBP-2 peptides as well as adoptive transfer of IGFBP-2-competent T cells mediated an antitumor effect in a transgenic mouse model of breast cancer. This is the first report of IGFBP-2 as a human tumor antigen that may be a functional therapeutic target in breast cancer.