ARTICLE ABSTRACTMycosis fungoides, the most common type of cutaneous T-cell lymphoma (CTCL), is characterized by a helper T-cell 2 (Th2) skewing with a mature CD4+ memory T-cell phenotype. Using skin samples from patients with mycosis fungoides (n = 21), healthy volunteers (n = 17), and individuals with atopic dermatitis (n = 17) and psoriasis (n = 9), we found IL32 mRNA expression significantly higher in mycosis fungoides samples than in samples from benign inflammatory skin diseases, and its expression increases with disease progression. By IHC and immunofluorescence, we confirmed IL32 protein expression in many CD3+CD4+ T cells and some epidermotropic T cells in mycosis fungoides lesions. MyLa cells (a mycosis fungoides cell line) express IL32, which, in turn, could promote cellular proliferation and viability in a dose-dependent fashion. IL32-treated MyLa and CTCL HH cells upregulated cell proliferation and survival genes. Of the major “polarizing” T-cell cytokines, only IFNγ mRNA increases with mycosis fungoides progression and positively correlates with IL32 mRNA expression. Th2 cytokines do not positively correlate with IL32 mRNA expression or mycosis fungoides progression. Furthermore, by flow cytometry, IL32 production by circulating activated T cells in healthy individuals was found in both IFNγ+ and IFNγ− cells but not in IL4+ or IL13+ cells. In conclusion, we have identified IL32+ cells as the likely tumor cells in mycosis fungoides, and demonstrated that IL32 mRNA expression increases with mycosis fungoides progression and is significantly higher than mRNA expression in other skin diseases, and that some IL32+ T cells are independent from the defined Th subsets. Thus, IL32 may play a unique role in mycosis fungoides progression as an autocrine cytokine. Cancer Immunol Res; 2(9); 890–900. ©2014 AACR.