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The bone derived hormone fibroblast growth factor 23 (FGF23) and its coreceptor Klotho represent a novel endocrine axis regulating mineral metabolism in health and disease. FGF23-Klotho signalling inhibits renal phosphate reabsorption and activation of vitamin D, and reduces secretion of parathyroid hormone. Serum levels of FGF23 rise in chronic kidney disease (CKD). In contrast, tissue expression of Klotho decreases in parallel with CKD progression and reaches low or undetectable levels in end stage renal disease. Numerous studies identify elevated FGF23 as a predictor of adverse clinical outcome. In particular, elevated FGF23 has recently been associated with greater risks of major cardiovascular events and mortality. However, there have been very few studies that have attempted to address the direct effects of FGF23 on myocardium. Moreover whether Klotho is involved in FGF23 – mediated actions on cardiomyocytes is still unclear. In this context, we investigate the role of FGF23 and Klotho in adult rat ventricular myocytes (ARVMs). Using video-edge-detection, epifluorescent microscopy and an Ionoptix® system, performed in isolated cardiomyocytes subjected to FGF23 or Klotho alone, or in association, we showed that FGF23 increases cell size and cell shortening in ARVMs, and induces arrhythmia in the presence of Isoprenaline. In addition Klotho prevents FGF23 effects on adult cardiomyocytes. Indeed, ARVMs subjected to Klotho showed marked protection from FGF23-induced hypertrophic responses and from FGF23- induced arrhythmias in the presence of Isoprenaline. Altogether these preliminary data provide a direct evidence of the role FGF23 in adult cardiomyocytes and suggest that Klotho may have a beneficial effect in preventing adverse cardiovascular outcomes in patients with or without CKD.