WSX-1 is a class I cytokine receptor with homology to the IL-12 receptors. The physiological role of WSX-1, which is expressed mainly in T cells, was investigated in gene-targeted WSX-1-deficient mice. IFN-γ production was reduced in isolated WSX-1^−/− T cells subjected to primary stimulation in vitro to induce Th1 differentiation but was normal in fully differentiated and activated WSX-1^−/− Th1 cells that had received secondary stimulation. WSX-1^−/− mice were remarkably susceptible to Leishmania major infection, showing impaired IFN-γ production early in the infection. However, IFN-γ production during the later phases of the infection was not impaired in the knockout. WSX-1^−/− mice also showed poorly differentiated granulomas with dispersed accumulations of mononuclear cells when infected with bacillus Calmette-Guerin (BCG). Thus, WSX-1 is essential for the initial mounting of Th1 responses but dispensable for their maintenance.