Aims: The putative protective role of esRAGE for cardiac autonomic function (CAF) remain unclear. To address this question, the present study has assessed the relationship of serum AGEs, sRAGE and esRAGE, and tissue AGEs with CAF in a high-risk population without diabetes. Material and methods: Forty eight subjects of mean age 52.7±11.2years and mean BMI 28.4±6.3kg/m2, divided into 2 groups according to glucose tolerance: 16 with normal glucose tolerance (NGT) and 24 with prediabetes, were enrolled. A standard OGTT was performed. The glucose tolerance was defined according to 2006 WHO criteria. Fasting, 120-min glucose, lipids, creatinine and HbA1c were measured. eGFR was calculated (CKD-EPI). Fasting, 120-min insulin (ECLIA method), esRAGE, sRAGE and AGEs (ELISA method) were assessed. HOMA-IR was calculated. Tissue AGEs were assessed by skin autofluorescence (AGE-Reader, DiagnOpticsTM). CAF was evaluated with ANSAR, applying deep breathing, Valsalva and standing. Results: There was a significant decline in CAF in prediabetes in comparison to NGT. Serum and tissue AGEs, sRAGE and esRAGE levels were similar between groups. On the matrix analysis, both sympathetic and parasympathetic activity at baseline and after standing and sympathetic tone during Valsalva were positively related to esRAGE in prediabetes. Multivariate regression analysis showed that esRAGE is an independent contributor to sympathetic, parasympathetic and total autonomic tone in prediabetes accounting for about 28%, 34% and 35% of their variances, respectively. Conclusion: Our results have demonstrated that CAF is decreased in prediabetes. esRAGE, but not sRAGE, is reciprocally related to CAF, probably opposing the negative effects of glycation.