Interleukin-9 (IL-9) is a T cell cytokine that acts through a γC-family receptor on target cells and is associated with inflammation and allergy. We determined that T cells from mice deficient in the T helper type 17 (TH17) pathway genes encoding retinoid-related orphan receptor γ (ROR-γ) and IL-23 receptor (IL-23R) produced abundant IL-9, and we found substantial growth inhibition of B16F10 melanoma in these mice. IL-9-blocking antibodies reversed this tumor growth inhibition and enhanced tumor growth in wild-type (WT) mice. Il9r-/- mice showed accelerated tumor growth, and administration of recombinant IL-9 (rIL-9) to tumor-bearing WT and Rag1-/- mice inhibited melanoma as well as lung carcinoma growth. Adoptive transfer of tumor-Antigen-specific TH9 cells into both WT and Rag1-/- mice suppressed melanoma growth; this effect was abrogated by treatment with neutralizing antibodies to IL-9. Exogenous rIL-9 inhibited tumor growth in Rag1-/- mice but not in mast-cell-deficient mice, suggesting that the targets of IL-9 in this setting include mast cells but not T or B cells. In addition, we found higher numbers of TH9 cells in normal human skin and blood compared to metastatic lesions of subjects with progressive stage IV melanoma. These results suggest a role for IL-9 in tumor immunity and offer insight into potential therapeutic strategies. © 2012 Nature America, Inc. All rights reserved.