The receptor for advanced glycation end-products (RAGE) is expressed to enhance degrees in human atherosclerotic plaques and co-localizes with inflammatory and pro-oxidant mediators in the vulnerable regions of the plaque. Previous studies highlighted a number of variants in the gene encoding the receptor, including a Gly to Ser substitution at amino acid 82 within the ligand-binding domain of RAGE. The Ser82 allele enhanced ligand-binding affinity and increased ligand-stimulated generation of inflammatory mediators in transfected cells and human monocytes compared to the common RAGE Gly82 allele. Thus it was logical to test the hypothesis that increased prevalence of the Gly82Ser polymorphism was associated with cardiovascular events in the Framingham offspring study (n=1632). Our analyses revealed that the Gly82Ser RAGE polymorphism did not demonstrate any association with the incidence of cardiovascular disease in diabetic or non-diabetic subjects (Gly82 96%, Ser82 4%). Analysis of specific manifestations of cardiovascular disease, including coronary heart disease (CHD), cardiovascular disease (CVD), myocardial infarction (MI) and ischemic disease (ISD) revealed no association with RAGE genotype. Further studies are required on other more prevalent genetic variants of RAGE and cardiovascular disease.