Acquired immunity to human schistosomiasis correlates with increased serum levels of schistosome antigen-specific IgE. Since interleukin (IL)-4 stimulates IgE production, the hypothesis that Th2-associated cell-mediated immunity participates in protection to reinfection was studied in a cohort of adolescent boys 12-18 months after chemotherapeutic cure in Upper Egypt. Initial Schistosoma haematobium prevalence was 51% and posttreatment incidence was 44%. Water contact was similar between putatively resistant and susceptible patients. Resistant persons had a 3.5- to 14-fold greater frequency of schistosome adult worm antigen (SWAP)-specific lymphocytes secreting IL-5 or IL-4 (by ELISPOT) and IL-5 or IL-4 production in peripheral blood lymphocyte culture supernatants (P < .05 to < .001, n = 48) versus susceptible subjects (n = 38). In contrast, SWAP-induced interferon-gamma and IL-10 production and lymphocyte proliferation were similar between the 2 groups. Schistosome egg antigen and streptolysin O each stimulated similar cytokine production in susceptible and resistant persons. Thus, enhanced SWAP-driven IL-4 and IL-5 production correlates with immunity to reinfection in adolescents exposed to urinary schistosomiasis.