C D4 T-cell help is required during the generation and maintenance of effective antitumor CD8 T cell–mediated immunity. The goal of this study was to determine whether HER-2/neu–specific CD8 T-cell immunity could be elicited using HER-2/neu–derived MHC class II “helper” peptides, which contain encompassed HLA-A2–binding motifs. Nineteen HLA-A2 patients with HER-2/neu–overexpressing cancers received a vaccine preparation consisting of putative HER-2/neu helper peptides p369–384, p688–703, and p971–984. Contained within these sequences are the HLA-A2–binding motifs p369–377, p689–697, and p971–979. After vaccination, the mean peptide-specific T-cell precursor frequency to the HLA-A2 peptides increased in the majority of patients. In addition, the peptide-specific T cells were able to lyse tumors. The responses were long-lived and detectable for more than 1 year after the final vaccination in select patients. These results demonstrate that HER-2/neu MHC class II epitopes containing encompassed MHC class I epitopes are able to induce long-lasting HER-2–specific IFN-γ–producing CD8 T cells.