While the precise mechanisms of vascular calcification (VC) in chronic kidney disease (CKD) remain to be elucidated, there is a close association between VC and secondary hyperparathyroidism (HPT). The elevations in calcium, phosphorus, the Ca x P product, and parathyroid hormone (PTH) observed in patients with CKD and secondary HPT have been associated with VC and increased risk of cardiovascular morbidity and mortality. We have investigated the development of extraskeletal calcification in uremic rats with secondary HPT treated with vitamin D derivatives (calcitriol or paricalcitol), calcimimetics (R-568 or AMG 641), or the combination of both types drugs. Treatment with calcitriol resulted in a significant increase in the extraosseous calcium and phosphorus content and high mortality. By contrast, treatment with calcimimetics, which provided a better control of plasma PTH levels, did not result in extraskeletal mineral accumulation and did not cause mortality. More important, when added to calcitriol, calcimimetics prevented the development of VC and reduced mortality. Paricalcitol administration to uremic rats resulted in calcification levels and mortality rates that were lower than in rats treated with calcitriol but higher than in rats treated with calcimimetics. The mechanism(s) of action responsible for the anticalcification effect of calcimimetics are likely related to the fact that these drugs can control PTH levels without increasing the plasma Ca x P product. In addition calcimimetic activation of vascular calcium-sensing receptor may also modulate the expression of proteins that prevent the development of VC, like matrix Gla protein.