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Interleukin-32 is a novel inflammatory mediator that has been described to be important in the immunopathogenesis and control of infections caused by Leishmania parasites. By performing experiments with primary human cells in vitro, we demonstrate that the expression of IL-32 isoforms is dependent on the time exposed to L. amazonensis and L. braziliensis antigens. Moreover, for the first time we show the functional consequences of three different genetic variations in the IL32 (rs4786370, rs4349147, rs1555001) modulating IL-32γ expression, influencing innate and adaptive cytokine production after Leishmania exposure. Using a Brazilian cohort of 107 American Tegumentary Leishmaniasis patients and a control cohort of 245 healthy individuals, the IL32 rs4786370 genetic variant was associated with protection against ATL, whereas the IL32 rs4349147 was associated with susceptibility to the development of localized cutaneous and mucosal leishmaniasis. These novel insights may help improve therapeutic strategies and lead to benefits for patients suffering from Leishmania infections. Author summary: In this study, we described how IL-32 isoforms are crucial to host defense against new world Leishmania species infections. Furthermore, by accessing the genotype frequency of genetic variations in IL32 in a cohort of Brazilian patients with American Tegumentary Leishmaniasis (ATL) and controls, we have obtained indications that IL-32 is associated with disease susceptibility and the development of different clinical manifestations. Thus, this study provides us an extra evidence that the isoforms of IL-32 shape the immune response favoring the development of different cytokines produced by peripheral blood mononuclear cells that might contribute to skin/mucosal inflammation and host defense. [ABSTRACT FROM AUTHOR]