C57BL/6 mice infected with Schistosoma mansoni naturally develop mild CD4+ T-cell-mediated immunopathology characterized by small hepatic granulomas around parasite eggs. However, immunization with soluble egg Ag in CFA markedly exacerbates the lesions by inducing a potent proinflammatory environment with high levels of IFN-γ and IL-17, which are signature cytokines of distinct Th1- versus Th17-cell lineages. To determine the relative role of these subsets in disease exacerbation, we examined mice deficient in T-bet (T-bet−/−), which is required for Th1 differentiation and IFN-γ production. We now report that immunization with soluble egg Ag in CFA caused a significantly greater enhancement of egg-induced hepatic immunopathology in T-bet−/− mice compared with WT controls, and analysis of their granulomas disclosed a higher proportion of activated DC and CD4+ T cells, as well as a marked influx of neutrophils. The absence of IFN-γ in the T-bet−/− mice correlated with a marked increase in IL-23p19, IL-17 and TNF-α in granulomas and MLN. In contrast, T-bet−/− mice had lower levels of IL-4, IL-5 and IL-10 and a reduction in FIZZ1 and FoxP3 expression, suggesting diminished regulatory activity, respectively, by alternatively activated macrophages and Treg. These findings demonstrate that T-bet-dependent signaling negatively regulates Th17-mediated immunopathology in severe schistosomiasis.