Abstract The quantitative tissue uptake of soluble immune complexes made with rabbit γG antibodies, was studied in normal and complement-depleted rabbits. The immune complexes that were cleared quickly from the circulation were primarily localized in the liver; less than 1% of the injected complexes was found within the lungs, kidneys or spleen. The tissue distribution of complexes made with intact antibodies was unchanged in complement-depleted rabbits. Soluble complexes made with reduced and alkylated antibodies fixed complement ineffectively. There was no hepatic uptake of HSA-anti-HSA and decreased uptake of γG-anti-γG and γM-anti-γM complexes, made with reduced and alkylated antibodies. In the latter two instances residual hepatic uptake was due to human γG or γM antigens in the complexes. It was concluded that the in vivo interaction of the fixed tissue macrophages and γG class of antibodies in soluble immune complexes was not mediated by circulating complement components. However, studies with a Waldenström's macroglobulin suggested that the in vivo interaction of macrophages and γM depended upon the third component of complement. It appeared that the complexes had to contain more than two γG antibody molecules for rapid uptake by the RES to occur. The RES uptake of complexes did not depend on their physical size. The rapidly removed complexes fixed complement strongly in vitro, although their in vivo uptake by the RES did not depend on an intact complement system in the circulation.