Reducing sugars react with amino groups in proteins, lipids, and nucleic acids to produce advanced glycation end products (AGEs), including N(epsilon)-carboxymethyl lysine (CML), which have been implicated in oxidative stress and vascular damage. The aim of this study was to determine whether genetic factors influence serum CML levels in normal subjects. We performed a classical twin study of CML in healthy nondiabetic female twins, 39 monozygotic and 45 dizygotic pairs, aged 21-74 years. Serum CML levels were estimated by enzyme-linked immunosorbent assay. Twin correlations (r) for serum CML levels were higher in monozygotic (r = 0.71) compared with dizygotic (r = 0.50) twin pairs, suggesting a substantial genetic effect and confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 74% (95% CI 58-84) of population variance in CML. Heritability (%) of fasting glucose (51%) and HbA(1c) (62%) could not explain CML heritability, which was not associated with them. CML levels are, therefore, predominantly genetically determined and independent of genes influencing fasting glucose or HbA(1c). Thus familial, largely genetic factors influence AGE implicating these glycoxidation products in the genetic contribution to macro- and microvascular disease.