Serum amyloid P component (SAP) binds toStreptococcus pyogenes, and we show here that it also binds toNeisseria meningitidis, including a lipopolysaccharide (LPS)-negative mutant, and to rough variants ofEscherichia coli. Surprisingly, this binding had a powerful antiopsonic effect bothin vitroandin vivo, reducing phagocytosis and killing of bacteria. Furthermore, SAP knockout mice survived lethal infection withS. pyogenesand roughE. coliJ5, organisms to which SAP binds. The susceptibility of SAP−/−mice was fully restored by injection of isolated human SAP. However, SAP−/−mice were more susceptible than wild-type animals to lethal infection withE. coliO111:B4, a smooth strain to which SAP does not bind, suggesting that SAP also has some host defense function. Although SAP binds to LPSin vitro, SAP−/−mice were only marginally more susceptible to lethal LPS challenge, and injection of large amounts of human SAP into wild-type mice did not affect sensitivity to LPS, indicating that SAP is not a significant modulator of LPS toxicityin vivo. In contrast, the binding of SAP to pathogenic bacteria enabled them to evade neutrophil phagocytosis and display enhanced virulence. Abrogation of this molecular camouflage is thus potentially a novel therapeutic approach, and we show here that administration to wild-type mice of (R)-1-[6-(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, a drug that inhibits SAP binding, significantly prolonged survival during lethal infection withE. coliJ5.