This study was conducted to examine the relationship between endogenous secretory receptors for advanced glycation end products (esRAGE) and oxidative stress in type 2 diabetic patients (T2DM) with/without advanced macro-angiopathy. Sixty-one T2DM were assessed for glycemic control, lipid profile, AGEs, carboxymethyl-lysine (CML), soluble receptor for advanced glycation end products (sRAGE), esRAGE and vitamin E levels, and underwent echo-color-Doppler of the abdominal aorta and aorto-iliac tree, carotid and lower limb arteries to check for evidence of plaques. AGEs and CML levels were significantly higher in T2DM with plaques than in those without (P = 0.0156 and P = 0.007, respectively) despite a comparable metabolic control and history of disease. EsRAGE and vitamin E levels were lower in T2DM with than in those without plaques (P < 0.0001), while no differences were observed as regards sRAGE levels. Considering all T2DM, univariate regression analysis showed a positive correlation between esRAGE and vitamin E (r = 0.456, P < 0.001), and a negative correlation between esRAGE and AGEs (r = -0.284, P < 0.05). After dividing patients by the presence/absence of plaques, esRAGE only correlated directly with vitamin E (r = 0.563, P < 0.01) and CML (r = 0.479, P < 0.05) in patients without plaques. This is the first study to establish a relationship between esRAGE and oxidative stress and/or antioxidant power, suggesting that esRAGE upregulation might be part of the cell's antioxidative defenses against plaque forming as a result of oxidative stress in the T2DM phenotype (cases with a more efficient esRAGE production being better protected). Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.