Although the α2β1 integrin is widely expressed and has been extensively studied, it has not been previously implicated in mast cell biology. We observed that α2 integrin subunit-deficient mice exhibited markedly diminished neutrophil and interleukin-6 responses during Listeria monocytogenes- and zymosan-induced peritonitis. Since exudative neutrophils of wild-type mice expressed little α2β1 integrin, it seemed unlikely that this Integrin mediated neutrophil migration directly. Here, we demonstrate constitutive α2β1 integrin expression on peritoneal mast cells. Although α2-null mice contain normal numbers of peritoneal mast calls, these α2-null cells do not support in vivo mast cell-dependent Inflammatory responses. We conclude that α2β1 Integrin provides a costimulatory function required for mast cell activation and cytokine production In response to infection.