OBJECTIVE To evaluate the role of melatonin, an antioxidant agent, in diabetic oxidative stress and vascular damage. METHODS Diabetes was induced in 21 male Wistar rats by intraperitoneal (IP) administration of streptozotocin and then the rats were equally and randomly allocated to diabetic, melatonin, and vehicle groups. Seven healthy normal rats with similar features comprised the control group as the fourth group. All animals were followed for 12 weeks. The melatonin group received IP melatonin daily and the vehicle group received 2.5% ethanol IP at the last month. At the end of 12 weeks, the rats were killed and retinas were harvested. The retinas were investigated for the existence of hypoxia-inducible factor 1-α (HIF-1α), vascular endothelial growth factor A (VEGF-A), and pigment epithelium-derived factor (PEDF) by ELISA. Retinal oxidative stress is quantitated by measuring nitrotyrosine and malondialdehyde levels. Retinal immunohistochemistry with antibody against CD31 antigen was carried out on retinal cross-sections. For statistics, ANOVA test was used for multiple comparisons. RESULTS Hyperglycemia increased retinal oxidation as measured through levels of nitrotyrosine and malondialdehyde. Diabetic retinas are also associated with abnormal vascular changes such as dilatation and deformation. HIF-1α, VEGF-A, and PEDF were all increased because of diabetic injury. Melatonin showed a potential beneficial effect on retinopathy in diabetic rats. It decreased retinal nitrotyrosine and malondialdehyde levels, showing an antioxidative support. The vasculomodulator cytokines are decreased accordingly by melatonin therapy. Melatonin normalized retinal vascular changes as well. CONCLUSIONS Melatonin may show some advantage on diabetic vascular changes through decreasing oxidative stress and vessel-related cytokines.