Although CD8+ T cells are usually considered antitumoral, several recent studies report that the cells can also promote tumor progression. Using the melanoma cell line B16 as a murine model of pulmonary metastasis, we examined whether the pro- versus antitumoral effects of CD8+ T cells relate to their Ag specificity. Results of the study indicate that although CD8+ T cells specific for tumor Ags promote tumor rejection, CD8+ T cells specific for unrelated Ags promote tumor progression. We found the effect to be partly attributable to CD8+ T cells dampening effective antitumor NK cell responses. Notably, activation of CD8+ T cell responses by an unrelated stimulus, in this case infection with influenza virus, increased the number of pulmonary tumor nodules. These data provide a rationale for previously unexplained data identifying contrasting roles for CD8+ T cells in tumor progression.