Intravenous immune globulin (IVIG), a polyvalent solution of pooled human immunoglobulin, is a potent immunomodulating agent. It is currently approved to treat autoimmune diseases, including idiopathic thrombocytopenia purpura, autoimmune hemolytic anemia, and Kawasaki disease. The basis of IVIG's immunomodulatory properties is not entirely understood. Proposed mechanisms include Fc receptor blockade, interference with cytokine network, and provision of anti-idiotypic antibodies. IVIG has also been shown to affect T-lymphocyte function, although a direct effect has been difficult to reconcile given the lack of immunoglobulin or Fc-receptors on T cells. Experiments were thus carried out to determine whether IVIG was acting on a specific T-cell subset and at the level of the T-cell receptor (TCR), and whether cytokine expression patterns were modulated. T lymphocytes obtained from adult peripheral blood and umbilical cord blood were cultured over a 1-wk time course in the presence of pharmacological IVIG concentrations (Gamunex®, 0-2.0mg/ml). Cells were exposed to various stimulation conditions, and TCR signaling competence was assessed by quantifying activation-induced upregulation of CD25 and CD69, as well as production of specific T-cell cytokines. IVIG was found to significantly decrease T-lymphocyte proliferation, in a dose and time-dependent manner, in both cord and adult blood. IVIG markedly reduced phytohemagglutinin and anti-CD3-induced upregulation of CD25 and CD69 in both CD4 and CD8 T-cell subsets, although phorbol ester-induced responses were intact, suggesting a defect in the CD3/TCR signaling pathway. IVIG also inhibited anti-CD3-induced cytokine production of IL-10, IL-2, and IFN-γ in a dose-dependent manner. These data suggest that IVIG may have direct T-cell immunomodulatory properties by dampening TCR responses. Further studies are needed to more precisely define the molecular targets of IVIG. © 2011 John Wiley & Sons A/S.