Pentraxins act as soluble pattern recognition receptors with a wide range of functions in various pathophysiological conditions. The long-pentraxin PTX3 shares the C-terminal pentraxin-domain with short-pentraxins C-reactive protein and serum amyloid P component and possesses an unique N-terminal domain. These structural features suggest that PTX3 may have both overlapping and distinct biological/ligand recognition properties when compared to short-pentraxins. PTX3 serves as a mechanism of amplification of inflammation and innate immunity. Indeed, vessel wall elements produce high amounts of PTX3 during inflammation and the levels of circulating PTX3 increase in several pathological conditions affecting the cardiovascular system. PTX3 exists as a free or extracellular matrix-associated molecule and it binds the complement fraction C1q. PTX3 binds also apoptotic cells and selected pathogens, playing a role in innate immunity processes. In endothelial cells and macrophages, PTX3 upregulates tissue factor expression, suggesting its action as a regulator of endothelium during thrombogenesis and ischaemic vascular disease. Finally, PTX3 binds the angiogenic fibroblast growth factor-2, thus inhibiting its biological activity. Taken together, these properties point to a role for PTX3 during vascular damage, angiogenesis, atherosclerosis, and restenosis.