We have identified the integrin α v β 3 as a ligand for mouse gp49B1, thus identifying a new class of ligand for a member of the family of inhibitory immunoreceptors that bear C2-type immunoglobulin-like domains. The specific interaction was shown by both cell-protein and cell-cell binding assays. In addition, we found that the interaction of α v β 3 with gp49B1 on bone marrow–derived mouse mast cells inhibited antigen-induced immunoglobulin E–mediated cell activation. Because neither gp49B1 nor α v β 3 exhibit substantive allelic variation, their newly appreciated interaction may reflect an innate pathway for down-regulating the activity of mast cells.