In order to more fully understand the host defense mechanisms against gonococcal infections, we decided to define the role of the classic and alternate complement pathways in gonococcal BA. Sera and infecting isolates were collected from several patients with genital and disseminated gonococcal infections. Sera from two never-infected subjects and a hypogammaglobulinemic patient were also collected. Sera from patients with genital gonorrhea and never-infected controls demonstrated marked BA for gonococci after 30 min incubation. Chelation of these sera with MgEGTA delayed the expression of BA. Consumption of C3, but not C4, was observed in chelated samples. BA could not be demonstrated in any of the sera from DGI patients or the patient with hypogammaglobulinemia. Aliquots of fresh and chelated hypogammaglobulinemic serum to which IgM or IgG antigonococcal antibodies were added showed marked BA by 30 and 60 min, respectively. Absorption of chelated serum with a serum-sensitive isolate eliminated the previously observed delayed BA. The findings suggest that gonococcal serum BA is primarily associated with activation of the classic complement pathway. Activation of the alternate pathway also occurs; however, its expression is delayed and appears to be antibody-dependent.