Abstract STAT4 and STAT6 are essential for the development of CD4+ Th1 and Th2 development, respectively. Tumor immunologists have hypothesized that Th1 cells are critical in tumor immunity because they facilitate differentiation of CD8+ T cells, which are potent anti-tumor effectors. We have used STAT4−/− and STAT6−/− mice to test this hypothesis. BALB/c and knockout mice were challenged in the mammary gland with the highly malignant and spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma. Primary tumor growth and metastatic disease are reduced in STAT6−/− mice relative to BALB/c and STAT4−/− mice. Ab depletions demonstrate that the effect is mediated by CD8+ T cells, and immunized STAT6−/− mice have higher levels of 4T1-specific CTL than BALB/c or STAT4−/− mice. Surprisingly, Th1 or Th2 cells are not involved, because CD4 depletion does not diminish the anti-tumor effect. Therefore, deletion of the STAT6 gene facilitates development of potent anti-tumor immunity via a CD4+-independent pathway.