Abstract Using genetically pure BALB/c mice deficient in IL-4 (IL-4−/−) or IL-4 receptor α-chain (IL-4Rα−/−), we have observed different disease outcomes to Leishmania major infection depending on the parasite substrain. Infection with L. major LV39 caused progressive, nonhealing ulcers and uncontrolled parasite growth in both IL-4−/− and IL-4Rα−/− mice. In contrast, infection with L. major IR173 was partially controlled in IL-4−/− mice but efficiently controlled in IL-4Rα−/− mice. Both IL-4−/− and IL-4Rα−/− mice infected with either substrain displayed reduced Th2 responses. Surprisingly, IFN-γ secretion was not up-regulated in the mutant mice, even in the IL-4Rα−/− mice, which were resistant to L. major IR173. The lack of increased IFN-γ production suggests that cytokine cross-regulation may not be operating in this model and that the effective ratios of Th1/Th2 cytokines become more indicative of disease outcome. The partial vs complete resistance to IR173 in IL-4−/− or IL-4Rα−/− mice implies that, in addition to IL-4, IL-13 may be involved in disease progression during L. major infection. The results with LV39 infection indicate that yet another unidentified factor is capable of causing susceptibility to L. major in the absence of IL-4 or IL-4 signaling.