Aims: To evaluate the influence of metabolic syndrome (MetS) as well as inflammatory and renal markers on cardiovascular disease (CVD) incidence. Methods and results: During 2001-2002, 1514 men and 1528 women (>18y) without any clinical evidence of CVD or any other chronic disease, at baseline, living in greater Athens area, Greece, were enrolled. In 2011-2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Incidence of fatal or non-fatal CVD was defined according to WHO-ICD-10 criteria. MetS was defined using three definitions, provided by the National Cholesterol Education Program Adult Treatment panel III (revised NCEP ATP III), the International Diabetes Federation (IDF) or the Harmonized definition. Furthermore, the contributory predictive role of C-reactive protein (CRP), inteleukin-6, uric acid and estimated glomerular filtration rate in the aforementioned models was evaluated. History of MetS-NCEP was positively associated with CVD, adjusting for potential confounding factors (OR:1.83, 95%CI:1.24-2.72). Not statistically significant associations with CVD incidence were observed when using the IDF or the Harmonized definition. Additionally, none of the added inflammatory and renal function markers mediated the influence of MetS on CVD incidence (all p's from Sobel test >0.40). C-statistic values for the MetS definitions used exceeded 0.789 (CI:0.751-0.827), indicating fair-to-good predictive probability of the models. Conclusion: Results of the present work revealed the negative impact of MetS-NCEP, but not of the other MetS definitions, on CVD incidence, a key-point that may help in better understanding the role of IDF and Harmonized MetS definitions on CVD.