The role of opsonophagocytosis (OP) in protection against meningococcal disease is controversial because patients with deficiencies in terminal complement proteins whose sera support OP but not bactericidal activity (BA) are at greatly increased risk of disease. We assayed complement-mediated BA and OP bactericidal activity in sera from 32 adults immunized with an outer membrane vesicle vaccine given alone or combined with an investigational recombinant protein, genome-derived neisserial antigen (GNA2132). The sera were heat inactivated to remove internal complement activity, and BA was measured with exogenous nonimmune human serum as a complement source. OP was measured with human polymorphonuclear cells (PMNs) and C6-depleted complement, which without PMNs did not support BA. Before immunization, 9 to 19% of sera from subjects in both vaccine groups combined had BA titers of >or=1:4, which increased to 41 to 72% after immunization (P < 0.01 against each of three test strains). The percentages of sera with OP titers of >or=1:5 were 3 to 16%, which increased to 55 to 72% (P < 0.001 for each strain). Most postimmunization BA-positive sera were OP positive, but 10 to 37% of BA-negative sera also were OP positive. Comparing the two vaccine groups, there were no significant differences in the percentages of sera with BA or OP activity except for a higher percentage of OP against one strain in postimmunization sera from subjects in the combination vaccine group (P <or= 0.02). The data support independent roles for serum BA and OP bactericidal activity in protection against group B disease.