The BCL-6 gene negatively regulates Th2 responses as shown by the finding that BCL-6-deficient (BCL-6−/−) mice develop a lethal Th2-type inflammatory disease. The response of inbred mouse strains to infection with Leishmania major is under genetic control; BALB/c mice are susceptible and develop a progressive parasite burden, whereas most other common laboratory strains of mice are resistant to infection. We found that BCL-6−/− mice on a resistant genetic background (C57BL/6× 129 intercrossed mice) were highly susceptible to L. major infection; they resembled BALB/c mice in terms of lesion size, parasite load, and the production of Th2 cytokines. BCL-6−/− IL-4−/− double-mutant mice were also susceptible to L. major infection and produced 10-fold higher levels of the Th2 cytokine IL-13 than IL-4−/− littermate controls. By contrast, BCL-6−/− STAT6−/− double-mutant mice were resistant to L. major infection despite also producing elevated levels of IL-13. These results show that STAT6 is required for susceptibility to L. major infection and suggest that IL-13 signaling through STAT6 may contribute to a nonhealing, exacerbated L. major infection.