Deficiency in α-Klotho is involved in the pathogenesis of vascular calcification. Since intermedin (IMD)_1–53 (a calcitonin/calcitonin gene-related peptide) protects against vascular calcification, we studied whether IMD_1–53 inhibits vascular calcification by upregulating α-Klotho. A rat model of chronic kidney disease (CKD) with vascular calcification induced by the 5/6 nephrectomy plus vitamin D₃ was used for study. The aortas of rats with CKD showed reduced IMD content but an increase of its receptor, calcitonin receptor-like receptor, and its receptor modifier, receptor activity-modifying protein 3. IMD_1–53 treatment reduced vascular calcification. The expression of α-Klotho was greatly decreased in the aortas of rats with CKD but increased in the aortas of IMD_1–53-treated rats with CKD. In vitro, IMD_1–53 increased α-Klotho protein level in calcified vascular smooth muscle cells. α-Klotho knockdown blocked the inhibitory effect of IMD_1–53 on vascular smooth muscle cell calcification and their transformation into osteoblast-like cells. The effect of IMD_1–53 to upregulate α-Klotho and inhibit vascular smooth muscle cell calcification was abolished by knockdown of its receptor or its modifier protein, or treatment with the protein kinase A inhibitor H89. Thus, IMD_1–53 may attenuate vascular calcification by upregulating α-Klotho via the calcitonin receptor/modifying protein complex and protein kinase A signaling.