Immediate early response gene X-1 (IEX-1) is a stress-inducible gene abundantly expressed in macrophages and T cells following various stimuli. To explore a potential role for IEX-1 in control of the susceptibility to Leishmania major infection, the inflammatory response during cutaneous leishmaniasis was evaluated in 129Sv/C57BL/6-resistant mice in the presence or absence of IEX-1. Null mutation of IEX-1 enhanced the susceptibility of the mice to L. major infection, and aggravated inflammatory responses in comparison with wild-type control mice. The excessive inflammation was not ascribed to a Th2-biased immune response or a defect in Th1 polarization, but rather to an elevated level of IL-17 production by both gammadelta T and CD4(+) cells, concomitant with an increase of the neutrophil recruitment early in the infection. The lack of IEX-1 also suppressed TNF-alpha production in both macrophages and T cells, resulting in a high intralesional load of parasites and delayed healing of the lesion, both of which were reversed by TNF-alpha treatment. These findings indicate the crucial role of IL-17 and TNF-alpha in determining the outcome of L. major infection beyond a balance between Th1- and Th2-mediated immune responses.