Endotoxemic shock is a systemic inflammatory response that is associated with increased nitric oxide (NO) and vasodilator prostaglandin production by inducible NO synthase and inducible cyclooxygenase (COX‐2) which contribute to the fall in blood pressure, vascular hyporeactivity and multiple organ failure. We have previously demonstrated that NO is involved in endotoxin‐induced changes in lipid peroxidation during endotoxemia in rats. The purpose of this study was to investigate whether COX‐2‐derived prostaglandins contribute to increase in lipid peroxidation via NO production in endotoxemic rats. Endotoxin caused an increase in nitrite (an index of NO production) and malonedialdehyde (MDA; an index of lipid peroxidation) levels as well as myeloperoxidase (MPO; an index of neutorphil infiltration) activity in the lung, spleen and femoral artery. Endotoxin‐induced increase in nitrite and MDA levels in these tissues of endotoxin‐treated rats was prevented by COX‐2 inhibitor, NS‐398. NS‐398 also prevented the effect of endotoxin to increase in MPO activity in these tissues. The data suggest that prostaglandins derived from COX‐2 contribute to the endotoxin‐induced changes in lipid peroxidation via NO production during endotoxemia.This study was supported by Mersin University Research Foundation (2006‐3, B Tunctan).