During natural schistosome infection, the induction of T helper type 2 (Th2) responses has been ascribed to parasite eggs, because exposure of the host to this life-cycle stage elicits a polarized Th2 response to egg antigens. In the present study, we show that schistosome worms also elicit systemic, antigen-specific type 2 responses during prepatent infection, before egg deposition begins. CD4(+) T cells producing interleukin (IL)-4 were induced by both male and female worms during single-sex infections, demonstrating that this response is independent of exposure to eggs. The Th2 response was accompanied by production of immunoglobulin E and the sensitization of circulating basophils to produce additional IL-4 in response to schistosome antigens. Together, our data show that schistosome worms establish an immunologic milieu where CD4(+) T cells and basophils are both primed to produce IL-4 before eggs are laid, suggesting that worms play a role in establishment of the Th2 response that is critical for host survival and parasite transmission.