AGEs are involved in diabetic complications and might be responsible for the phenomenon of 'hyperglycaemic memory'. D-Carnosine-octylester (DCO) has been shown to attenuate AGE formation and vascular and renal injury induced by high-fat diet in Apoe-null mice. This study aimed to verify the protective effect of DCO in atherosclerosis and renal disease induced by experimental diabetes and to discover whether reduction of AGE formation by early vs late DCO treatment provides better macro and microvascular protection. Apoe-null mice were rendered diabetic by streptozotocin and were left untreated or were treated with DCO for 20 weeks (DCO-Extended), from week 1 to 11 (DCO-Early) or from week 9 to 19 (DCO-Late). Non-diabetic Apoe-null mice served as controls. Aortic and renal lesions were evaluated by morphometry and protein and gene expression of disease markers were assessed by immunohistochemistry and real-time PCR. DCO-Extended treatment produced a more stable plaque phenotype by markedly attenuating diabetes-induced increases in lesion size, necrotic core area and plaque content of Nε-carboxymethyllysine, levels of apoptotic cells and markers of inflammation and oxidative stress and also reductions in collagen and smooth muscle cells. DCO treatment for 11 weeks afforded partial protection and this was significantly better in DCO-Early mice than in DCO-Late mice. Renal disease was attenuated in DCO-Extended mice and to a lesser extent in those treated for 11 weeks, with no significant difference between DCO-Early mice and DCO-Late mice. These data show that DCO protects mice from diabetes-induced vascular and renal disease and that protection against atherosclerosis is more effectively achieved by early treatment than by late treatment, thus suggesting that early inhibition of AGE formation attenuates progression of macroangiopathy and favours development of more stable lesions.