T he leukocyte integrin α_Mβ₂/Mac-1 appears to support the inflammatory response through multiple ligands, but local engagement of fibrin(ogen) may be particularly important for leukocyte function. To define the biological significance of fibrin(ogen)-α_Mβ₂ interaction in vivo, gene-targeted mice were generated in which the α_Mβ₂-binding motif within the fibrinogen γ chain (N³⁹⁰RLSIGE³⁹⁶) was converted to a series of alanine residues. Mice carrying the Fibγ ^390–396A allele maintained normal levels of fibrinogen, retained normal clotting function, supported platelet aggregation, and never developed spontaneous hemorrhagic events. However, the mutant fibrinogen failed to support α_Mβ₂-mediated adhesion of primary neutrophils, macrophages, and α_Mβ₂-expressing cell lines. The elimination of the α_Mβ₂-binding motif on fibrin(ogen) severely compromised the inflammatory response in vivo as evidenced by a dramatic impediment in leukocyte clearance of Staphylococcus aureus inoculated into the peritoneal cavity. This defect in bacterial clearance was due not to diminished leukocyte trafficking but rather to a failure to fully implement antimicrobial functions. These studies definitively demonstrate that fibrin(ogen) is a physiologically relevant ligand for α_Mβ₂, integrin engagement of fibrin(ogen) is critical to leukocyte function and innate immunity in vivo, and the biological importance of fibrinogen in regulating the inflammatory response can be appreciated outside of any alteration in clotting function.