Intravenous IgG has been adopted as treatment for various immune-related diseases, including immune thrombocytopenic purpura, autoimmune neuropathies, systemic lupus erythematosus, Guillain-Barré syndrome, myasthenia gravis, Kawasaki disease, skin blistering diseases. The intravenous administration of exogenously pooled human immunoglobulin was originally licensed as antibody replacement therapy in patients with primary immunodeficiencies, but in the last thirty years, despite a current lack of institutional approval, off-label IVIgG treatment of a consistent number of disorders has shown to be a useful approach with good clinical results. The mechanism of action of IVIgG is complex and is not fully understood. The current understanding and development in the immune modulant action of IVIgG has three basic mechanisms: 1) F(ab')2 mediated actions; 2) interaction of IgGFc molecule with Fc receptors (FcgammaR); 3) actions mediated by complement fractions binding within the Fc molecular structure. The mode of action of IVIgG involves expression and function of Fc receptors, idiotype network, complement and cytokine network, T and B cell differentiation, modulation of antigen-presenting cells (APC). The therapeutic action of IVIgG is also related to natural antibodies in maintaining immune homeostasis. In addition, IVIgG interaction through V regions with complementary V regions of antibodies may provide a rational basis for selection of various immune repertoires. Since there is a significant gap between the institutional approval and the use of IVIgG in various clinical conditions, for which there is no adequate testing or for which a small number of records does not allow a rigorous statistical approach, several public and private institutions (mostly insurance companies) and research centres have developed guidelines for evaluating a rational and deontological approach in various pathological situations where IVIgG is used. Mathematical models based on non-linear differential equations may represent another potentially useful system to better understand an IVIgG targeted use in individual subjects.