We investigated whether secretion of multiple cytokines by CD8+ T cells is associated with improved protection against tumor challenge. We show that antitumor immunity induced by immunization with dendritic cells and a MHC class I-binding tumor peptide are dependent on secretion of IFN-γ but not IL-4 or IL-5 by host cells. To further address the role of IL-4 and IL-5 in antitumor immunity, tumor-specific TCR-transgenic CD8+ T cells were activated in vitro to generate cytotoxic T (Tc) 1 cells that secrete high IFN-γ and no IL-4 or IL-5 or Tc2 cells that secrete IL-4, IL-5, and some IFN-γ. Both cell types killed target cells in vitro. Tc1 and Tc2 cells were adoptively transferred into syngeneic hosts, and their ability to protect against tumor challenge was compared. Tc1 cells were able to significantly delay tumor growth, whereas Tc2 cells or Tc2 cells from IFN-γ−/− donors had no effect. This was due to neither the inability of Tc2 cells to survive in vivo or to migrate to the tumor site nor their inability to secrete IL-4 and/or IL-5 in the presence of limiting amounts of anti-CD3. However, IFN-γ secretion by Tc2 cells was triggered inefficiently by restimulation with Ag compared with anti-CD3. We conclude that the ability to secrete “type 2” cytokines, and cytotoxic ability, have a limited role in antitumor immune responses mediated by CD8+ T cells, whereas the capacity to secrete high amounts of IFN-γ remains the most critical antitumor effector mechanism in vivo.