Leukocyte recruitment to inflammation sites depends on interactions between integrins and extracellular matrix (ECM). In this report we show that mice lacking the ECM protein mindin exhibit severely impaired recruitment of neutrophils and macrophages in 4 different inflammation models. Furthermore, neutrophils directly bind to immobilized mindin, and mindin matrix mediates neutrophil migration in vitro. The adhesion of neutrophils to mindin is blocked by anti–integrin α₄, anti–integrin α_M, and anti–integrin β₂ antibodies. We also show that HEK-293 cells transfected with cDNA encoding these integrins exhibit enhanced binding to immobilized mindin matrix and the increased binding can be blocked by anti-integrin antibodies. Our results suggest that mindin serves as a novel ligand for integrins and mindin-integrin interactions are critical for inflammatory cell recruitment in vivo.