Atherosclerosis is a complex process characterized by an increase in the wall thickness owing to the accumulation of cells and extracellular matrix between the endothelium and the smooth muscle cell wall. This process is associated with different pathologies and it is accelerated in patients with chronic renal failure. In these patients, decreased synthesis of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) leads to secondary complications, like hyperparathyroidism, and treatment with 1,25(OH)(2)D(3) is a common practice. The effect of 1,25(OH)(2)D(3) on vascular smooth muscle cells (VSMCs) calcification has been widely studied, but the role of 1,25(OH)(2)D(3) on VSMC proliferation remains obscure. We have analyzed the effects of 1,25(OH)(2)D(3) in the proliferation of VSMC. We found that 1,25(OH)(2)D(3) (5-100 nM) induces a dose-dependent increase in VSMC proliferation in quiescent cells and in cells stimulated to grow. This increase in proliferation is achieved by shortening the G1 phase. The effect of 1,25(OH)(2)D(3) on VSMC proliferation is mediated by an increase of the expression of vascular endothelial growth factor A (VEGF), as the inhibition of VEGF activity totally blunted the 1,25(OH)(2) D(3)-induced VSMC proliferation. We found this increase in proliferation in vitro, ex vivo in aortic rings incubated with 1,25(OH)(2)D(3), and in vivo in animals with a model of chronic renal failure (5/6 nephrectomy) treated with 1,25(OH)(2)D(3) (1 mug/kg three times a week for 8 weeks). Thus, we conclude that 1,25(OH)(2)D(3) induces increases in VSMC proliferation through an increase on VEGF expression.