Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is best known for its selective cytotoxicity against transformed tumor cells. Most non-transformed primary cells and several cancer cell lines are not only resistant to death receptor-induced apoptosis, but also subject to inflammatory responses in a nuclear factor-?B (NF-?B)-dependent manner. Although the involvement of TRAIL in a variety of vascular disorders has been proposed, the exact molecular mechanisms are unclear. Here, we aimed to delineate the role of TRAIL in inflammatory vascular response. We also sought possible molecular mechanisms to identify potential targets for the prevention and treatment of post-angioplastic restenosis and atherosclerosis. Treatment with TRAIL increased the expression of intercellular adhesion molecule-1 by primary human vascular smooth muscle cells via protein kinase C (PKC)d and NF-?B activation. Following detailed analysis using various PKCd mutants, we determined that PKCd activation was mediated by caspase-dependent proteolysis. The protective role of PKCd was further confirmed in post-traumatic vascular remodeling in vivo. We propose that the TRAIL/TRAIL receptor system has a critical role in the pathogenesis of inflammatory vascular disorders by transducing pro-inflammatory signals via caspase-mediated PKCd cleavage and subsequent NF-?B activation.