CONTEXT: Diabetes mellitus is characterized by oxidative stress, which in turn induces endothelial dysfunction. As a potent antioxidant compound, lycopene might rescue diabetic endothelial dysfunction by reducing oxidative stress. OBJECTIVE: The present study investigated whether lycopene could lower oxidative stress and attenuate endothelial dysfunction in diabetic rats. METHODS: Different doses of lycopene (10, 30, and 60 mg/kg/day, p.o.) were administered for 30 days to streptozotocin (STZ) (60 mg/kg)-induced diabetic rats. Biochemical parameters and aortic malondialdehyde (MDA) content, superoxidase dismutase (SOD) activity, nitric oxide (NO) levels, constitutive NOS (cNOS) activity, and inducible NOS (iNOS) activity were determined. Endothelium-dependent and endothelium-independent vasorelaxation were measured in aortas for estimating endothelial function. RESULTS: Compared with normal controls, endothelial function was significantly reduced in diabetic rats and the blunted endothelial function was dependently ameliorated with lycopene treatment. Compared with normal controls, the serum oxidized low-density lipoprotein (ox-LDL) levels, the aortic MDA levels, and iNOS activity in diabetic rats were increased by 113, 197, and 100%, respectively, whereas aortic SOD activity, NO levels, and cNOS activity were decreased by 73, 53, and 65%, respectively. Exogenous administration of lycopene to diabetic rats caused a dose-dependent decrease of serum glucose and ox-LDL levels, an increase of aortic SOD activity, NO levels, and cNOS activity, and a decrease of aortic MDA levels and iNOS activity. CONCLUSION: Chronic lycopene treatment could attenuate endothelial dysfunction by reducing oxidative stress in STZ-induced diabetic rats. These results indicate that chronic lycopene treatment might be useful in preventing diabetic vascular complications associated with endothelial dysfunction.