To define mechanisms by which polysaccharide capsules confer enhanced virulence on gram-negative bacteria, we examined the effect of the Escherichia coli capsule on complement fixation to the bacterial surface and on phagocytosis and killing of these bacteria by mouse macrophages and human polymorphonuclear leukocytes (PMN) and monocytes. When E. coli were attached to mouse macrophages with concanavalin A, the macrophages readily phagocytosed unencapsulated but not encapsulated bacteria even in the presence of fresh mouse serum; macrophages did not phagocytose encapsulated E. coli unless antibacterial or anti-Con A antibody was added. Similarly, when these bacteria were attached to human PMN with Con A, PMN ingested unencapsulated but not encapsulated E. coli. PMN phagocytosed and killed encapsulated serum-resistant E. coli only in the presence of both complement and antibacterial antibody; PMN phagocytosed and killed unencapsulated E. coli of the same strain in the presence of complement alone. Fluorescence microscopy showed that antibody had to be present for encapsulated but not unencapsulated E. coli to fix complement to its surface. To examine the role of the complement receptors of human PMN and monocytes in phagocytosis and killing of encapsulated E. coli, we used human and rabbit antibacterial immunoglobulin (Ig)M to fix complement to the bacteria. PMN and monocytes phagocytosed and killed encapsulated E. coli in the presence of both IgM and complement, but not in the presence of either serum opsonin alone. In the presence of antibacterial IgG, PMN and monocytes required complement to effectively phagocytose and kill the E. coli. We conclude that (a) attachment by itself results in ingestion of unencapsulated but not encapsulated E. coli; (b) under physiologic conditions, E. coli are not phagocytosed or killed the absence of antibody, the E. coli capsule blocks complement fixation to the bacterial surface probably by masking surface components, such as lipopolysaccharide, capable of activating the complement pathway; (d) the E. coli capsule imposes a requirement for specific antibacterial antibody for complement fixation; and (e) the complement receptor of human PMN and monocytes mediates phagocytoses of complement-coated encapsulated bacteria and is the primary mediator of phagocytosis and killing of these bacteria.