Traditionally, platelets are known to play an important role in hemostasis, thrombosis, and wound healing, but increasing evidence suggests that activated platelets also may promote inflammation. Platelet-induced modulation of inflammation seems to involve platelet expression of ligands in the tumor necrosis factor (TNF) superfamily such as CD40 ligand and Fas ligand. The present study demonstrates that LIGHT, another member of the TNF superfamily, is associated with platelets and is released as a soluble ligand on platelet activation. The release of LIGHT involves GP IIb/IIIa-dependent mechanisms and action of metal-dependent proteases as well as intracellular processes such as actin polymerization. We also report that platelet-derived LIGHT is biologically active and can induce an inflammatory response in monocytes and particularly within endothelial cells measured as up-regulation of adhesion molecules and release of chemokines. Moreover, we demonstrate that thrombus material, obtained at the site of plaque rupture in patients with acute myocardial infarction, contains platelet-associated LIGHT, suggesting that LIGHT-mediated inflammation also is operating in vivo within an inflamed and thrombotic vessel wall. The data may suggest a pathogenic role for platelet-derived LIGHT in atherogenesis and plaque destabilization as well as in other inflammatory disorders involving leukocyte infiltration into the vessel wall.