In a prospective study, we have examined the tumor-specific immune response in a group of 59 patients with human papillomavirus (HPV) 16-positive (HPV16⁺)–induced or HPV18⁺-induced cervical cancer. Local antitumor immunity was analyzed by the enumeration of tumor-infiltrating dendritic cells and CD4⁺, CD8⁺, and regulatory T cells as well as by calculation of the ratio of CD8⁺/CD4⁺ T cells and CD8⁺/regulatory T cells. Systemic tumor-specific immunity was assessed by determination of the HPV E6- and/or E7-specific T-cell response in the blood of these patients. Finally, these variables were evaluated with respect to known histopathologic prognostic variables, including the absence (LN⁻) or presence (LN⁺) of lymph node metastases. Stratification according to the lymph node status of patients revealed a significantly stronger CD8⁺ T-cell tumor infiltration, a higher CD8⁺/CD4⁺ T-cell ratio, and higher CD8⁺/regulatory T-cell ratio in the group of patients in which the tumor failed to metastasize to the tumor-draining lymph node. Subdivision according to the presence (IR⁺) or absence (IR⁻) of circulating HPV-specific T cells disclosed that the highest number of tumor-infiltrating CD8⁺ T cells was found in the group of LN⁻ patients displaying a concomitant systemic tumor-specific immune response (LN⁻IR⁺). CD8⁺ T-cell infiltration in LN⁻IR⁻ patients was comparable with that of LN⁺ patients. In cervical cancer, the absence of lymph node metastases is strongly associated with a better prognosis. Our data indicate that, especially in a subgroup of LN⁻ patients, a strong and effective interaction between immune system and tumor exists. This subgroup of cervical cancer patients may have the best prognosis. [Cancer Res 2007;67(1):354–61]