Granulocyte [polymorphonuclear leucocyte (PMN)] migration to sites of infection and subsequent activation is essential for host defense. Gene-targeted mice deficient for integrin-associated protein (IAP, also termed CD47) succumbed to Escherichia coli peritonitis at inoccula survived by heterozygous littermates. In vivo, they had an early defect in PMN accumulation at the site of infection. In vitro, IAP^−/− PMNs were deficient in β₃ integrin-dependent ligand binding, activation of an oxidative burst, and Fc receptor-mediated phagocytosis. Thus, IAP plays a key role in host defense by participating both in PMN migration in response to bacterial infection and in PMN activation at extravascular sites.