The populations of immune system cells necessary for induction of the Th2 response have yet to be fully defined. Among the most consistent natural stimuli for Th2 responses are helminth parasites, such as the gastrointestinal nematode Nippostrongylus brasiliensis. Strong Th2 bias in immune responsiveness to live parasite infection can be reproduced by injection of a soluble Nippostrongylus excretory/secretory product (NES) collected from adult worm parasites in vitro. Injection of soluble NES induces a residual type-2 response (IL-13) even in IL-4-deficient mice, and drives a fully polar Th2 response in IL-5-deficient animals. A potent IL-10 response is observed irrespective of IL-4 or IL-5 gene status. While MHC Class II knockout animals fail to mount any IL-4 or IL-10 response, the Th2 bias is intact in Class I knockouts, indicating that CD8+ or NK-like T cells restricted to classical or non-classical Class I molecules do not play an essential role in Th2 induction. B cell-deficient microMT animals also show responses, which are strongly skewed to IL-4 production. Thus, Th2 induction by Nippostrongylus antigens is independent of B cells, or MHC class I presentation, and does not require a sufficiency of eosinophils in vivo.