In the present study, we investigated the role of parathyroid hormone–related peptide (PTHrP) in vascular calcification by using an in vitro calcification model. We demonstrated that the expression of PTHrP decreased in the progression of bovine vascular smooth muscle cell (BVSMC) calcification and that inhibition of calcification by etidronate (EHDP) and levamisole restored PTHrP secretion, suggesting that the expression of PTHrP is associated with calcification. PTHrP (1-34) and PTH (1-34) dose-dependently inhibited BVSMC calcification. Protein kinase A (PKA) and protein kinase C (PKC) inhibitors completely blocked the inhibitory effect of PTHrP, suggesting that both PKA and PKC may be involved in its signaling pathway. Moreover, PTHrP inhibited alkaline phosphatase (ALP) activity, implying that the impact on ALP may contribute to its action on calcification. Furthermore, the PTHrP antagonist, PTHrP (7-34), dose-dependently increased calcium deposition by BVSMC. Interestingly, PTHrP production by BVSMC dramatically increased in the presence of EHDP, and PTHrP (7-34) partially antagonized the inhibitory effect of EHDP on BVSMC calcification. These results suggest that PTHrP may regulate vascular calcification as an autocrine/paracrine factor.