Background: Klotho gene was identified as an aging suppressor. In animals klotho over-expression extends lifespan and defective klotho results in rapid aging and early death. The kidney is the main contributor to circulating klotho levels and during chronic kidney disease, renal klotho gene expression is drastically reduced in animals and humans as well.Objective: We aimed to determine the consequences of a serum klotho defect on cardiovascular morbidity and mortality during chronic dialysis.Design: The ARNOGENE study was designed to prospectively follow a cohort of hemodialysis patients for 2 years without specific intervention. 769 patients were recruited and followed from the end of 2008 until January 2011. 238 patients were analysed due to a technical sample conservation issue with other samples.Results: The median serum klotho was markedly reduced, 360.4 ng/L [IQR176.5] as compared with non-dialysis chronic kidney disease patients or healthy volunteers. Patients with a serum klotho above the first quartile (≥280 ng/L) had a significantly reduced occurrence of outcome combining cardiovascular events and cardiovascular death (OR=0.39; 0.19-0.78, p=0.008) compared to patient with klotho <280 ng/L. This effect persisted (OR=0.86; 0.76-0.99, p=0.03) after adjustment on age, gender, diabetes, cardiac insufficiency, dialysis vintage, and serum hemoglobin, albumin, FGF-23, phosphate and calcium.Conclusions: These results suggest that during chronic hemodialysis, conservation of serum klotho above 280 ng/L is associated with a better 2-yr cardiovascular protection. Thus, a preserved klotho function supports cardiovascular protection and may represent a prognostic tool and therapeutic target for cardiovascular disease.