Hyaluronan (HA) occurs in the body as a large, hydrating, space-filling, carbohydrate polymer in the extracellular matrix; it has both anti-angiogenic and immunosuppressive properties. Cleavage of HA results in the generation of variably sized fragments that stimulate multiple angiogenic and inflammatory responses in a size-specific manner. In this study, we report that platelets, as well as their megakaryocyte precursors, are unusual among somatic cells in that they contain only hyaluronidase 2 (HYAL2) but not HYAL1. Platelet HYAL2 is sufficient to cleave HA into fragments that are specific for inflammatory and angiogenic signaling; this process occurs in the absence of HYAL1, which is necessary in all other tissues to perform further HA degradation. Platelets can bind to HA, some of which derives from the stressed microvessel endothelial cell surface. Platelet-derived HYAL2 cleaves HA into fragments that stimulate mononuclear leukocytes in the immediate microenvironment to produce proinflammatory cytokines, including interleukin-6 and interleukin-8. Platelets, thus, are not only involved in hemostasis, the earliest step in wound healing, but are also important in the signaling of subsequent inflammatory and angiogenic steps. We hypothesize that aberrations in these sequential steps can promote chronic inflammation, as found in inflammatory bowel disease. The platelet may thus provide an interface between acute and chronic inflammation, wound healing, and their subsequent fibrotic responses.