Complement-mediated bactericidal and opsonic activity of IgGI and IgG2 antibodies to Haemophilus infiuenzae type b polysaccharide (polyribosylribitol phosphate [PRP]) were investigated. The antibody sources were IgGI or IgG2 subclass polyclonal antibody fractions prepared by immunoabsorption of sera from adults immunized with PRP or PRP-diphtheria toxoid conjugate vaccine or clonally purified anti-PRP antibodies from eight adults immunized withPRP vaccine. In bactericidal assays using an inoculum of 3 A 103 colony-forming units (cfu)/ml, twofold lower concentrations of IgGl compared with IgG2 antibody were required for 50% killing. With rvl()6 cfu/ml, IgGI antibody killed 3 logs more of bacteria than were killed by comparable concentrations of IgG2 antibody. The IgGI antibody also required lower concentrations of complement than did the IgG2 antibody for comparable bacteriolytic activity. Clonally purified IgGI and IgG2 anti-PRP antibodies from most individuals showed similar relative differences in bactericidal activity. IgGI anti-PRP antibody was also more efficient than IgG2 anti-PRP antibody in enhancing the uptake of radiolabeled type b H. infiuenzae by human polymorphonuclear leukocytes in the presence of complement and in protecting infant rats from developing bacteremia. However, the differences in opsonic or protective activity of the two subclasses were smaller than the differences in bactericidal activity. Thus, IgGl anti-PRP antibody is functionally more effective than IgG2 antibody, but it is likely that both subclasses can confer protection against disease. © 1990 by The University of Chicago.