Neisseria gonorrhoeae isolated from patients with disseminated infection (DGI) often resist complement (C')-dependent killing by normal human serum (NHS) and less commonly by convalescent DGI serum. 7 of 10 NHS specimens completely inhibited killing of serum-resistant (ser(r)) gonococci by convalescent or immune DGI serum. Immunoglobulin G (IgG) purified from NHS was shown to be the blocking agent. In addition, IgM (plus C') purified from NHS was shown to be fivefold more effective (wt/wt) in killing serum-sensitive (ser(s)) gonococci than equivalent amounts of IgM tested in the presence of IgG (whole serum). Although inhibition of NHS killing of ser(s) gonococci required a 640% excess of IgG, only a 40% excess was required to block immune serum killing of ser(r) gonococci. F(ab')(2) prepared from IgG also blocked killing of ser(r) gonococci by immune serum indicating antigenic specificity of blocking IgG.IgG immunoconcentrated against outer membrane protein (OMP) derived from ser(r) gonococci showed 40-fold increased blocking activity over normal IgG (wt/wt) and lacked antibody activity directed against gonococcal lipopolysaccharide by ELISA. Using direct immunoabsorption of IgG with purified gonococcal OMP; ser(r)-OMP was found sixfold more effective than ser(s)-OMP in neutralizing the blocking of immune serum killing of ser(r) gonococci, and 10-fold more effective in systems that used excess blocking IgG, NHS, and ser(s) gonococci. Blocking IgG preabsorbed with whole ser(r) gonococci lost 75% of its ability to block immune serum killing compared with no loss in this system using a similar absorption with ser(s) gonococci. IgG purified from NHS contained fivefold higher titers of antibody against ser(r)-OMP than ser(s)-OMP by ELISA.