Significance Statement Vascular calcification is a major complication in CKD–metabolic bone disorder and an independent predictor of cardiovascular morbidity and mortality. In CKD, impaired calcium and phosphate homeostasis are associated with altered expression of the calcium-sensing receptor (CaSR) in the parathyroid glands and the kidney. The CaSR is also present in the vasculature, but its contribution to total body mineral ion homeostasis is unknown. We demonstrated that ablation of CaSR from vascular smooth muscle cells in knockout mice led to profound mineral ion imbalance. These results demonstrate a previously unknown mode of mineral ion regulation besides the parathyroid glands and the kidneys. Alterations in expression and activity of CaSR in vascular smooth muscle cells would be expected to contribute to mineral ion imbalance in CKD. Background Impaired mineral ion metabolism is a hallmark of CKD–metabolic bone disorder. It can lead to pathologic vascular calcification and is associated with an increased risk of cardiovascular mortality. Loss of calcium-sensing receptor (CaSR) expression in vascular smooth muscle cells exacerbates vascular calcification in vitro. Conversely, vascular calcification can be reduced by calcimimetics, which function as allosteric activators of CaSR. Methods To determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells ( SM22α CaSR Δflox/Δflox ). Results Vascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice in vitro. However, mice did not show ectopic calcifications in vivo but they did display a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating fibroblast growth factor 23 (FGF23), calcitriol (1,25-D₃), and parathyroid hormone levels. Renal tubular α-Klotho protein expression was increased in KO mice but vascular α-Klotho protein expression was not. Altered CaSR expression in the kidney or the parathyroid glands could not account for the observed phenotype of the KO mice. Conclusions These results suggest that, in addition to CaSR’s established role in the parathyroid-kidney-bone axis, expression of CaSR in vascular smooth muscle cells directly contributes to total body mineral ion homeostasis.