The development of hepatic fibrosis and portal hypertension is the principal cause of morbidity and mortality in schistosomiasis mansoni. Nevertheless, relatively little is known about the mechanisms that lead to excessive collagen deposition during infection with Schistosoma mansoni. In the murine model, infection leads to significant egg-induced granuloma formation, tissue eosinophilia, and hepatic fibrosis. The pathology has been linked to dominant type 2 cytokine expression, and our recent studies showed that sensitizing animals to egg Ags in combination with IL-12, before infection, led to a highly significant reduction in egg-induced immunopathology. In this study, we demonstrate that in contrast with egg/IL-12-sensitized animals that showed marked decreases in pathology, mice similarly sensitized but depleted of IFN-gamma, IL-12, or TNF-alpha at the time of egg laying developed granulomas that were similar to the non-IL-12-treated control group. Although all three anti-cytokine-treated groups exhibited a dominant type 1 response in lymph node cells restimulated ex vivo, the expression of type 2 cytokine mRNA was markedly restored at the site of granuloma formation, which suggests that all three cytokines are required to maintain the suppressed type 2 pattern. Moreover, egg/IL-12-sensitized mice depleted of IFN-gamma or IL-12 displayed a partial reduction in IFN-gamma production, suggesting that multiple type 1 cytokines were required to maintain polarized type 1 responses to chronic type 2-inducing stimuli. Together, these data reveal key roles for IFN-gamma, IL-12, and TNF-alpha in the protective effects mediated by this IL-12-based vaccine to prevent pathology.