Until recently, therapeutic cancer vaccines only sporadically led to long-term clinical responses. We here report on a novel vaccine modality, characterized by the administration of long (23-45 amino acids) synthetic peptides in incomplete Freund adjuvant (mineral oil-based, Montanide ISA-51), delivered subcutaneously. Such vaccines were first demonstrated to be much more potent in preclinical T-cell response induction and tumor therapy experiments than short major histocompatibility complex class I-binding peptides that have been used extensively in the clinic. A long-peptide vaccine consisting of 13 overlapping peptides, together covering the entire length of the 2 oncogenic proteins E6 and E7 of high-risk human papilloma virus type 16 (HPV16), caused complete regression of all lesions and eradication of virus in 9 of 20 women with high-grade vulvar intraepithelial neoplasia. The nature and strength of the vaccine-induced T-cell response were significantly correlated with the clinical response. This vaccine promises to be of use, not only in patients with premalignant lesions caused by high-risk HPV16, but also in patients with malignant tumors caused by this virus, including HPV16-positive cervical cancer, anal cancer, and head and neck cancer.