Studies were performed in in vitro and in vivo models to assess the effect of intravenous immunoglobulin (IVIG) on the development of acute complement-mediated tissue damage. IVIG significantly increased the duration of survival and frequently prevented the death of guinea pigs injected with anti-Forssman antiserum to cause lethal Forssman shock; no control animal treated with albumin and/or maltose vehicle survived. The most pronounced effect was achieve by delivering IVIG as one slow injection at 1,800 mg/kg 3 h before Forssman shock was elicited. Infusion of guinea pig IgG at the same dosage was similarly protective. A strong positive correlation was found between IgG plasma levels and survival time in guinea pigs treated with graded doses of IVIG. Therapy itself did not affect C3 and C4 levels nor the capacity to activate these components. In vitro studies showed almost complete inhibition of C3 uptake onto IgG-sensitized erythrocytes using serum from an IVIG-treated animal. We suggest that supraphysiologic levels of IVIG act in part by preventing active C3 fragments from binding to target cells. Infusion of high dose IVIG may be a rational approach to modulating acute, complement-dependent tissue damage in a variety of diseases in man.