The low frequency of tumor Ag-specific T cells in vivo has made it challenging to directly measure their clonal sizes and cytokine signatures. We used a new generation ELISPOT approach to study the constitutive immunogenicity of the RMA tumor in syngeneic B6 mice and adjuvant-guided immunity against an MHC class II-restricted RMA peptide, H11. 1. The RMA tumor was found to activate cells of the innate immune system and to induce a type 1 polarized, RMA-specific CD4 and CD8 T cell response. With clonal sizes∼ 10/10 6, the magnitude of this constitutively induced immune response did not suffice to control the tumor cell growth. In contrast, immunization with H11. 1 peptide, using an immunostimulatory CpG oligonucleotide or CFA as adjuvant, engaged∼ 25-or∼ 10-fold higher clonal sizes of type 1 polarized CD4 cells, respectively. Therefore, the CpG oligonucleotide functioned as a stronger type 1 adjuvant and, unlike CFA, elicited protective immunity. The protection was IFN-γ dependent, as it was not inducible in IFN-γ knockout mice. Therefore, CpG adjuvant-guided induction of type 1 immunity against tumor Ags might be a promising subunit vaccination approach.