Several naturally occurring antibodies stimulate alternative complement pathway C3b deposition. One type of these antibodies, human anti-band 3 antibody, is involved in opsonizing senescent and oxidatively stressed red cells with C3b (Proc. Natl. Acad. Sci. USA 84[1987]7368). The mechanism was investigated, by which it stimulates alternative complement pathway. Anti-band 3 antibodies are preferred targets for nascent C3b which forms ester bonds with IgG and generates C3b-IgG complexes. Since C3b-IgG and free C3b can equally well nucleate alternative convertases and since C3b in C3b-IgG is protected from degradation (J. Exp. Med. 160[1984]1640), generation of C3b-IgG complexes means stimulation of alternative complement pathway. Anti-band 3 antibodies are preferred targets for the shortlived, nascent C3b since they bind to native C3 by a site distant from the antigen binding site. In vitro generation of C3b-IgG complexes confirmed a preferential formation of C3b-anti-band 3 complexes. Thus, an affinity for C3 may be all what is required to make an antibody a stimulator of the alternative complement pathway and thereby a potent opsonin.