Granuloma formation around schistosomal eggs is induced by soluble egg antigens (SEA) and mediated by the activity of CD4⁺ Th lymphocytes and their cytokines. Regulation of the inflammatory Th cell response during infection is still insufficiently understood. The hypothesis of this study was that activation-induced cell death (AICD) of CD4⁺ T cells is involved in the immune inflammatory response. This study investigated the dynamics of splenic and granuloma CD4⁺ Th cell apoptosis and Fas ligand (FasL) expression during the acute and chronic stages of murine schistosomal infection. Enhanced apoptosis of freshly isolated CD4⁺ Th lymphocytes commenced after egg deposition and persisted during the peak and modulated phases of granuloma formation. After oviposition, CD4⁺, CD8⁺, and CD19⁺ splenocytes and granuloma cells expressed elevated levels of FasL but FasL expression declined during the downmodulated stage of infection. In culture, SEA induced splenic and granuloma CD4⁺ T-cell apoptosis and stimulated expression of FasL on splenic but not granuloma CD4⁺ T cells, CD8⁺ T cells, and CD19⁺ B cells. SEA-stimulated splenocytes and granuloma cells preferentially lysed a Fas-transfected target cell line. Depletion of B cells from SEA-stimulated splenic cultures decreased CD4⁺ T cell apoptosis. Coculture of purified splenic B cells with CD4⁺ T cells and adoptive transfer of purified B cells indicated that antigen-stimulated B cells can kill CD4⁺ Th cells. However, CD4⁺ T cells were the dominant mediators of apoptosis in the granuloma. This study indicates that AICD is involved in the apoptosis of CD4⁺ T cells during schistosomal infection.