Neutrophils (PMN) express a βj-like integral (Leukocyte-Response Integrin/LRI) with ligand binding specificity for the RGD sequence within many extracellular matrix proteins. Multiple extracellular matrix and clotting molecules, as well as the specific peptide ligand KOAGDVA, stimulate Fc-receptor-mediated phagocytosis, oxidative burst, and/or chemotaxis via LRI. Integrin-Associated Protein (CD47) is a multiply membrane-spanning immunoglobulin family member widely expressed in vivo. Physically and functionally IAP associates with LRI. Anti-IAP mAb inhibit ligand binding to and stimulation of phagocytosis and respiratory burst via LRI. Anti-IAP also blocks transendothelial migration of human PMN in vitro. We have generated gene-targeted mice deficient in the expression of IAP/CD47. These mice are viable, with normal development, histology, blood cell counts, and fertility. PMN from these mice fail to bind KGAGDVA-coated targets, or to augment Fc-receptor-mediated phagocytosis and oxidative burst in response to LRI ligands, whereas the response is normal to control stimuli. PMN influx to the peritoneal cavity was normal in thioglycollate and zymosan-induced peritonitis in IAP-deficient mice. However, IAP-deficient deficient mice succumbed to intraperitoneal challenge with E. coli K-l, at doses that were survived by IAP-sufficient littermates. This host defense defect may be the consequence of impaired PMN migration to or activation at extravascular sites, i.