The development of Schistosoma mansoni ova-induced granulomas is regulated by cytokines secreted by distinct Th cell subsets. To determine the importance of Th1 and Th2 cells in granuloma formation, we have studied the immune response to S. mansoni ova in Stat4-and Stat6-deficient mice, which lack Th1 and Th2 cells, respectively. Lymphocytes from both naive and infected Stat6-deficient mice produced minimal levels of Th2 cell cytokines and Ag-specific IgG1 and IgE, but showed enhanced production of IFN-γ and Ag-specific IgG2a and IgG2b following schistosome egg injection. This shift away from a Th2 cell-mediated immune response was coupled with the development of pulmonary and hepatic granulomas that were greatly decreased in size compared with those in control littermates. Hepatic granulomas in Stat6-deficient mice were composed of predominantly mononuclear cells with very sparse appearance of eosinophils, and their diminished size was accompanied by decreased amounts of liver hydroxyproline content as a measure of collagen deposition. In contrast, lymphocytes from infected Stat4-deficient mice produced Th2 cell cytokines in amounts comparable to those produced by control littermates, but low levels of IFN-γ. While infected Stat4-deficient mice developed pulmonary granulomas following schistosome egg injection that were modestly impaired in size, the granuloma size and amount of collagen deposition in the liver were equivalent to those seen in control littermates. These studies demonstrate that Th2 cells are required for the full development of the granulomas and tissue-destructive fibrotic pathology associated with the immune response to S. mansoni ova.