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Despite technical and pharmacological improvements achieved over the past years, long-term prognosis of patients undergoing chronic hemodialysis is still rather poor. Cardiovascular disease is the leading cause of both morbidity and mortality in these patients, mostly because of their severely compromised cardiovascular conditions already at the time of starting hemodialysis. A proper management of factors involved in the development of cardiovascular abnormalities is therefore a basic pre-requisite for improving their clinical outcome. Hypertension and anemia should be adequately evaluated and corrected, in light of their primary involvement in the pathogenesis of left ventricular hypertrophy, whereas treatment of calcium and phosphate metabolism disorders, particularly of high serum phosphorus levels, is needed to prevent the development of severe secondary hyperparathyroidism and mainly vascular calcifications, whose detrimental pathophysiologic consequences on cardiovascular structures are huge. At the same time, the prescription of the hemodialytic treatment should be optimised, with a satisfactory removal of uremic toxins through the delivery of an adequate dialysis dose and with the use of biocompatible membranes, where possible, thus minimizing the inflammatory response secondary to the interaction between blood and the artificial material of the hemodialysis system. The clinical superiority of high-flux membranes, although suggested by all studies performed so far, has still to be demonstrated by well-conducted clinical studies; on-line convective treatments and daily hemodialysis, although promising, also need to be confirmed in randomized trials. In conclusion, long-term outcome of hemodialysis patients may only be improved by a complex, multi-factorial therapeutical approach.