Idiopathic or immune thrombocytopenic purpura (ITP) is characterized by antibody-mediated destruction of platelets. The etiology is unknown. We postulated that increased autoantibody production in ITP might be attributable to either increased or prolonged expression of CD40 ligand (CD40L, CD154) in T or B lymphocytes, as has been previously observed in systemic lupus erythematosus (SLE). In addition, we hypothesized that ITP is characterized by increased levels of interleukin 4 (IL-4), a prototypic Th2 cytokine which, along with CD40 ligation, is required for B cell differentiation and production of several IgG subclasses. Cell surface CD154 expression was measured in freshly-isolated and in vitro-activated peripheral blood lymphocytes of sixteen ITP patients and eight healthy volunteers. Plasma levels of IL-4 and the prototypic Th1 cytokine interferon-gamma (IFNgamma) were determined. We observed that CD154 expression in unstimulated and in vitro-activated lymphocytes did not differ between ITP patients and healthy controls. Plasma levels of the Th2 cytokine IL-4 were significantly higher in the ITP patients. These studies indicate that overexpression of CD154 in lymphocytes is unlikely to be a primary pathophysiological defect in most patients with ITP. The data support that in addition to cell membrane antigens such as CD154, soluble cytokines such as IL-4 should be considered as potential targets for therapy in this disease.