Given that specific subsets of T helper 1 (Th1) and T helper 2 (Th2) CD4⁺ T cells have been shown to play key roles in tumor rejection models, we wanted to assess the contribution of either Th1 or Th2 CD4⁺ cell subtypes for redirected T-cell immunotherapy. In this study, we have developed a novel method involving retroviral transduction and in vitro T-cell polarization to generate gene-engineered mouse CD4⁺ Th1 and Th2 cells or T helper intermediate (Thi) cells expressing an anti–erbB2-CD28-ζ chimeric receptor. Gene-modified Th1 and Th2 polarized CD4⁺ cells were characterized by the preferential secretion of IFN-γ and interleukin-4, respectively, whereas Thi cells secreted both cytokines following receptor ligation. In adoptive transfer studies using an erbB2⁺ lung metastasis model, complete survival of mice was observed when transduced Th1, Th2, or Thi CD4⁺ cells were transferred in combination with an equivalent number of transduced CD8⁺ T cells. Tumor rejection was consistently associated with transduced T cells at the tumor site and interleukin-2 secretion. However, the surviving mice treated with gene-modified Th1 CD4⁺ cells were significantly more resistant to a subsequent challenge with a different erbB2⁺ tumor (4T1.2) implanted s.c. This result correlated with both increased expansion of Th1 CD4⁺ and CD8⁺ T cells in the blood and a greater number of these cells localizing to the tumor site following rechallenge. These data support the use of gene-modified CD4⁺ Th1 and CD8⁺ T cells for mediating a sustained antitumor response. [Cancer Res 2007;67(23):11428–37]