LA419 is a novel nitric oxide-donor with antioxidant properties. The effect of this compound on the development of atherosclerosis was investigated in apolipoprotein E-deficient mice. Male mice were randomized to receive vehicle or 5 mg/kg/day LA419 for 12 weeks. At the end of this period, plasma lipid and lipoprotein parameters, oxidative stress markers and hepatic fat, and mRNA levels were measured as well as en face and cross-sectional lesion areas of the aorta. Data showed that LA419 administration reduced atherosclerotic foci and cross-sectional lesion areas by decreasing the intimae presence of macrophage-derived foam cells despite an increase in plasma cholesterol. This agent induced a significant reduction in body weight gain and mass of adipose tissue. Furthermore, compared with placebo, LA419 administration significantly reduced plasma triglycerides and apolipoprotein C-III levels as well as systemic oxidative stress, estimated by plasma 8-isoprostane. Conversely, nonesterified fatty acid and HDL cholesterol levels remained unchanged, as well as apolipoproteins A-I, A-IV, and B and paraoxonase activity. Plasma triglycerides were significantly associated with plasma levels of apolipoprotein C-III and hepatic Fsp27 mRNA expression. These results indicate that administration of LA419 modulates lesion development. These actions are partly independent of total cholesterol as well as HDL particles and related to triglyceridemia and oxidative stress. Hypotriglyceridemia is associated with an equal number of apoB-containing particles. Hence, LA419 administration could be used as a safe alternative to control the metabolic syndrome and atherosclerosis.