Intravenous immunoglobulin (IVIg) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases in addition to supportive therapy of immunodeficient patients. Although a considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory functions in these diseases, they remain not fully elucidated. The mode of action of IVIg is complex, involving interference with activation of complement and the cytokine network, modulation of: idiotype network, expression of Fc receptors, and activation, differentiation and effector functions of T and B cells and of antigen-presenting cells such as dendritic cells. The therapeutic effects of IVIg most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy individuals.