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Vaccination with heat shock proteins (HSP) protects mice from challenge with the tumor from which the HSP were isolated. The antigenicity of HSP vaccination is thought to result from HSP-associated endogenous major histocompatibility complex class I peptides or their precursors. The vaccination effect can be achieved in an adjuvant-free manner and is mediated by CD8+ T cells, indicating that HSP can act as a natural adjuvant and cross-prime T cells in vivo. We previously devised a recombinant vaccine composed of a CD8+ T cell epitope fused to the carboxyl-terminus of hsc70 and demonstrated efficient generation of antigen-specific cytotoxic T lymphocyte (CTL) after vaccination with a few micrograms of the hsc70-CTL epitope fusion protein. The present study aimed to determine if the fusion protein vaccine could control tumor growth in vivo and whether simultaneous fusion of a CD4+ T cell epitope to the amino terminus of the hsc70-CTL epitope would be a more potent vaccine compared to the CTL epitope alone. Ovalbumin (OVA)–derived 8 mer peptide, OVA257-264, and 16mer peptide, OVA265-280, were used as CD8+ and CD4+ T cell epitopes, respectively. Vaccination with hsc70-OVA257-264 generated peptide specific CTL more effectively than a peptide plus incomplete Freund's adjuvant combination, and suppressed growth of OVA expressing EL4 (E.G7) and B16 melanoma tumor cells. Addition of OVA265-280 to the amino-terminus of hsc70-OVA257-264 (OVA265-280-hsc70-OVA257-264) enhanced the generation of the OVA257-264-specific CTL population, leading to better eradication of MO5 lung metastasis compared to hsc70-OVA257-264. Our results suggest that fusion of both CD4+ and CD8+ T cell epitopes to hsc70 enhances tumor immunity beyond the effect of the CD8+ T cell epitope alone. (Cancer Sci 2008; 99: 1008–1015)