Macrophage/neutrophil-specific IL-4 receptor α-deficient mice (LysM^CreIL-4Rα^−/flox) were generated to understand the role of IL-4/IL-13 responsive myeloid cells during Type 2 immune responses. LysM^CreIL-4Rα^−/flox mice developed protective immunity against Nippostrongylus brasiliensis accompanied by T_H2 development and goblet cell hyperplasia. In contrast, LysM^CreIL-4Rα^−/flox mice were extremely susceptible to Schistosoma mansoni infection with 100% mortality during acute infection. Mortality was not dependent on neutrophils and occurred in the presence of T_H2/Type 2 responses, granuloma formation, and egg-induced fibrosis. Death was associated with increased T_H1 cytokines, hepatic and intestinal histopathology, increased NOS-2 activity, impaired egg expulsion, and sepsis. IL-10 was not able to compensate for the absence of IL-4/IL-13-activated alternative macrophages. Together, this shows that alternative macrophages are essential during schistosomiasis for protection against organ injury through downregulation of egg-induced inflammation.