Platelets are known contributors of hemostasis but have recently been shown to be important in inflammation and infectious diseases. Moreover, thrombocytopenia is often observed in patients with sepsis. We previously reported that platelets actively phagocytosed IgG-coated latex beads. In this study, the capacity of human platelets to participate in host defense against bacterial infections was determined by assessing their ability to kill Escherichia coli. Washed human platelets were incubated with unopsonized or IgG-opsonized E similar to coli and evaluated for binding and killing of E.similar to coli. We found that although both unopsonized and IgG-opsonized E.similar to coli were associated with platelets, only IgG-opsonized E.similar to coli were efficiently killed unless platelets were activated by a potent agonist. The bactericidal activity was dependent on Fc?RIIA, was sensitive to cytochalasin D, but was not due to reactive oxygen metabolites. These data suggest that platelets may play an important role in protection against infection.