The relative contribution of IL-4 and IL-13 to the regulation of IgE synthesis has remained relatively poorly characterized, partially because of lack of suitable animal models. We have studied the roles of IL-4 and IL-13 in human IgE synthesis induced by supernatants derived from activated CD4+ or CD8+ T cell clones. Neutralizing anti-IL-4 and anti-IL-13 monoclonal antibodies (mAbs) inhibited IgE synthesis induced by anti-CD40 mAbs and supernatants from CD4+ T cells by an average 61% and 42%, respectively (n = 25). Recombinant IL-13 had additive effects on IL-4-induced IgE synthesis, but only when IL-4 was present at low concentrations. Accordingly, IL-4 was the dominant IgE synthesis-inducing cytokine derived from highly polarized T helper (TH)2 cells. However, anti-IL-13 mAbs also significantly inhibited IgE synthesis induced by two of three supernatants derived from allergen-specific T(H2)-like cell lines generated from the skin of patients with atopic dermatitis. Furthermore, anti-IL-13 mAbs almost completely inhibited IgE synthesis induced by supernatants from T(H1) cells or CD8+ T cell clones. Taken together, these data indicate that IL-13, in addition to IL-4, contributes to IgE synthesis induced by all T helper cell subsets, including allergen-specific T(H2) cells. Moreover, IL-13 appears to be the major IgE synthesis-inducing cytokine derived from T(H1) cells or CD8+ T cells.