IL-4 receptor α-chain-deficient (IL-4Rα−/−) mice were generated by homologous and site-specific recombination, using the Cre/loxP system in BALB/c-derived embryonic stem cells. In vitro analysis of cells from these mice revealed impaired IL-4-and IL-13-mediated functions, demonstrating that the IL-4Rα-chain is an essential component of both the IL-4 and the IL-13 receptor. Whereas Leishmania major-infected BALB/c mice developed fatal progressive disease with type 2 Ab responses within 3 mo, both IL-4Rα−/− and IL-4−/− BALB/c mice contained infection with reduced footpad swelling, parasite load, moderate histopathology, and type 1 Ab responses during this time period. Conclusively, these results demonstrate an IL-4-dependent mechanism of susceptibility in BALB/c mice. Nevertheless, in contrast to mutant mice, infected C57BL/6 mice healed completely within 3 mo, indicating that additional factors are necessary for subsequent healing and elimination of the pathogen. During the further course of infection, IL-4Rα−/− mice developed progressive disease with massive footpad swelling. Lesions became ulcerative and necrotic with subsequent destruction of connective tissue and bones, as well as dissemination into organs and consequent mortality within the monitored 6 mo of chronic infection. In striking contrast, IL-4−/− mice maintained control of infection on a moderate level, but were unable to clear the pathogen. The distinct phenotypes of the BALB/c embryonic stem cell-derived IL-4−/− and IL-4Rα−/− mouse strains identify previously unsuspected mechanisms for maintaining host immunity to chronic infection with L. major, mediated by a functional IL-13 receptor.