Abstract Modification of a few tryptophan residues in rabbit IgG and Fc with 2-hydroxy-5-nitrobenzyl bromide (NBB) eliminates the anti-complementary activity of these protein molecules in the presence of whole guinea pig complement, but does not significantly alter their Clq-binding capacity. When bound to tryptophan-modified IgG aggregates, Clq retains its hemolytic activity as a function of the number of modified tryptophan residues. IgG aggregates that contained about five modified tryptophan residues per IgG molecule retained almost 80 per cent of their Clq-binding capacity and the bound Clq remained fully hemolytically active. In order to locate the Clq-binding site of IgG, peptic fragments of IgG were tested for their ability to inhibit the interaction of Clq with aggregated IgG. When compared on a molar basis, fragment Pep III′ (C-terminal part) of Fc). Modification of two tryptophan residues in Pep V did not reduce its affinity for Clq. These finding suggest that unmodified tryptophan residues in Pep V are not implicated in the binding of Clq but are probably essential for the correct conformation of the Clq-binding site. Furthermore, the Clq-binding site of IgG seems to be made up of amino acid residues from different regions of Fc and the integrity of the entire Fc is a prerequisite for the activation of Cl.