We previously showed that M3 protein bound both fibrinogen and human serum albumin. Here, I report that M3 protein also has affinity for human immunoglobulin G. In contrast, M3 protein did not show affinity for polyclonal immunoglobulin G from other mammalian species (rabbit and goat). On the human immunoglobulin G molecule, the Fab domain was mainly responsible for the interaction with M3 protein, although the Fc region had a low degree of interaction with the M3 protein. Also, since the 35 kDa C-terminal fragment of M3 protein bound human immunoglobulin G, the binding site for human immunoglobulin G on M3 protein is present in this portion of the protein. The M3 protein-human immunoglobulin G complexes initiated complement activation via both classical and alternative pathways in normal human serum. When C3 was precipitated in the fluid phase with anti-C3 antibody and analyzed by SDS-PAGE under reducing conditions, M3 protein coprecipitated with the complexes and was polymerized. However, there was no polymerization of M3 protein when incubated with normal human serum treated with magnesium-ethyleneglycol-bis-(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid in the presence of M3 protein. Thus, this polymerization is mostly mediated via the classical activation pathway. It is probably helpful for the understanding of the antiphagocytic activity of M protein.