The pathogenesis of multiple organ dysfunction syndrome (MODS) in septic shock is complicated and not fully understood. Some studies show that an overproduction of nitric oxide (NO) leads to the refractory hypotension and multiple organ failure, while other studies suggest that free radicals, e.g. superoxide (O(2)(-)), contribute to the detrimental effect on vascular responsiveness and tissue/organ damage. Thus, this study was performed on the Wistar rat by using cecal ligation and puncture (CLP) to induce septic shock-associated MODS. We evaluated the effect of an antioxidant melatonin in CLP-induced septic rats and demonstrated that melatonin (3 mg/kg, i.v. at 3, 6, 12 hr after CLP) significantly (a) attenuated hyporeactivity to norepinephrine and delayed hypotension, (b) reduced plasma index of hepatic and renal dysfunction, (c) diminished plasma NO and interleukin-1beta (IL-1beta) concentrations as well as aortic O(2)(-) levels, (d) reduced marked infiltration of polymorphonuclear neutrophils (PMNs) in the lung and liver tissues, and (e) promoted the survival rate at 18 hr to twofold compared with the CLP alone group. The current study underlined the inhibition of plasma NO and IL-1beta as well as aortic O(2)(-) production and the reduction of PMN infiltration may lead to the amelioration of MODS, which may contribute to the beneficial effect of antioxidants (e.g. melatonin in this study) in conscious rats with peritonitis-induced lethality. Thus, the antioxidant could be a novel agent for the treatment of septic animals or patients in the early stage.