Although protective immunity in C57BL/6 mice induced by a single dose of the radiation-attenuated schistosome vaccine is believed to be mediated by Th1-type immune responses, we here report that in BALB/c mice protection can also depend upon signaling via the interleukin-4 (IL-4) receptor which conventionally governs the development of Th2-type immune responses. We show that in BALB/c mice deficient for the IL-4 receptor alpha chain (IL-4Ralpha(-/-)), which are unresponsive to IL-4 and IL-13, vaccine-induced protection is abrogated compared with that in wild-type (WT) mice. In vaccinated IL-4Ralpha(-/-) mice, IL-12p40 production by cells from the skin exposure site was elevated, although gamma interferon (IFN-gamma) production in draining lymphoid tissues was similar in WT and IL-4Ralpha(-/-) mice. Nevertheless, the effector response in IL-4Ralpha(-/-) mice was Th1 biased with elevated IFN-gamma in the lungs and higher immunoglobulin G2a (IgG2a) and IgG2b titers but negligible quantities of Th2-associated IgG1 and IgE. Interestingly, levels of IL-4 were equivalent in WT and IL-4Ralpha(-/-) mice, indicating that Th2 responses were not dependent upon signaling by IL-4 or IL-13. No differences in the phenotype and composition of the pulmonary effector mechanism that might explain the failure to induce protection in IL-4Ralpha(-/-) mice were detected. However, passive transfer of partial protection to naive IL-4Ralpha(-/-) mice, using serum from vaccinated WT mice, indicates that Th2-associated antibodies such as IgG1 have a role in parasite elimination in BALB/c strain mice and that signaling via IL-4R can be an important factor in the generation of protection.