Abstract: Melatonin (MT) is the principal secretory product of the pineal gland and its role as an immumo-modulator is well established. Recent evidence shows that MT exerts protective effects in septic shock, hemorrhagic shock and inflammation. Lipopolysaccharide (LPS), from Escherichia coli, administered to animals directly stimulates a number of cells and systems to produce various inflammatory mediators. LPS-induced septic shock is characterized by hypotension and vascular hyporeactivity to contracting agents. In particular, the reactive oxygen species such as superoxide and nitric oxide (NO) contribute to the pathophysiology of septic shock. In this study, we demonstrate that MT pretreatment prevents the hyporeactivity to phenylephrine in vivo and in aorta rings collected from rats treated with the endotoxin. The beneficial effect of MT seems related to its antioxidant properties and with inhibition of inducible nitric oxide synthase (iNOS) protein expression, reduction of NO production and nitrotyrosine formation, in aorta, preventing vascular, and endothelial injury. Additionally, we first demonstrate, that MT inhibited nuclear enzyme poly (ADP-ribose) synthetase activation in vascular tissue. The current study underlined the protective effect of MT on the vascular dysfunction associated with septic shock, data that could support the clinical use of MT in human endotoxemia.