Endotoxin is a potent inducer of lipid peroxidation (LPO), which is associated with the development of endotoxemia. 3,4-Methylenedioxyphenol (sesamol) is one of the sesame oil lignans with a high anti-LPO effect. Whether sesamol can attenuate endotoxin-induced LPO and multiple organ injury is unknown. After a dose response for sesamol in endotoxin-challenged rats was established, experiments were conducted to assess its effects on hydroxyl radical, peroxynitrite, and superoxide anion counts, activities of superoxide dismutase, catalase, and glutathione peroxidase, as well as the production of nitric oxide (NO) and the expression of inducible NO synthase. In addition, the effects of sesamol on endotoxin-induced hepatic and renal injuries were assessed. Sesamol (a) dose dependently reduced serum LPO inendotoxin-challenged rats, (b) decreased hydroxyl radical and peroxynitrite, but not superoxide anion counts, (c)increased the activities of superoxide dismutase, catalase, and glutathione peroxidase in endotoxin-treated rats, (d)reduced NO production and inducible NO synthase expression, and (e) attenuated hepatic and renal injuries induced by endotoxin in rats. We concluded that sesamol might protect against organ injury by decreasing NO-associated LPO in endotoxemic rats.