Intravenous immunoglobulin (IVIg) is a blood product prepared from the serum of between 1000 and 15 000 donors per batch. It is the treatment of choice for patients with antibody deficiencies. In this indication, IVIg is used at a ‘replacement dose’ of 200–400 mg/kg body weight, given approximately 3-weekly. In contrast, ‘high-dose’ IVIg (hdIVIg), given most frequently at 2 g/kg/month, is used as an ‘immunomodulatory’ agent in an increasing number of immune and inflammatory disorders. Initial use of hdIVIg was for idiopathic thrombocytopenic purpura (ITP) in children.1 Despite a lack of double-blind, randomized, placebo-controlled trials, many other conditions are managed with hdIVIg, including numerous haematological, rheumatological, neurological and dermatological disorders.2 In this article, we review the current understanding and recent developments in the immunomodulatory mechanisms of action of hdIVIg. IVIg may, for the purposes of clarity, be considered to have four separate mechanistic components: (1) actions mediated by the variable regions F(ab′)2, (2) actions of Fc on a range of Fc receptors (FcR), (3) actions mediated by complement binding within the Fc fragment, and (4) immunomodulatory substances other than antibody in the IVIg preparations (Fig. 1). It is likely that these components act concurrently, however, different mechanisms may be important in different settings. We will address the mechanisms under these broad headings although in some cases more than one mechanism is operative or our understanding does not allow accurate categorization. Figure 1 Immunomodulatory actions of intravenous immunoglobulin. Intravenous immunoglobulin (IVIg) may for the purposes of understanding be thought of as four separate components: (1) actions mediated by the variable regions F(ab′)2, (2) actions of Fc ... F(ab′)2 Mediating Binding Site Interactions of IVIg Anti-proliferative effects IVIg has been shown to have a considerable inhibitory effect on mitogen-induced T-cell proliferation in vitro.3 This effect has been shown for intact immunoglobulin G (IgG), with less evidence for a role for Fc fragment.4 Single-donor preparations of IVIg inhibited proliferation more than commercial multiple-donor preparations, but there was no difference between standard IVIg preparations and cytomegalovirus hyperimmune globulin.4 Both antigen-dependent and antigen-independent responses are inhibited by IVIg in a dose-dependent manner.5 T-cell proliferation in response to anti-CD3 or tetanus toxoid was shown to be inhibited by IVIg in a dose-dependent manner over a range of IgG concentrations (0–10 mg/ml).6 The inhibition was reversible by exogenous interleukin-2 (IL-2) and the authors concluded that the effects were a result of interference with cytokine-mediated T-cell proliferation. Both pooled normal human immunoglobulin, and single donor immunoglobulin were shown to reduce pokeweed mitogen (PWM) -induced plaque-forming cell formation following 300 mg/kg infusions into patients with common variable immunodeficiency.7 This effect was short-lived, and sera collected >24 hr post-infusion no longer inhibited cell proliferation. The suppressive effects of IVIg when used at replacement dose (100–200 mg/kg) were demonstrated in antibody-deficient children.8 In this study, the effects of the children's sera on the immunoglobulin-producing activity of PWM-stimulated normal lymphocytes was assessed. Even this low-dose IVIg was shown to enhance the suppressive activity of the patient's lymphocytes, an effect that was reversed on cessation of IVIg therapy.