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OBJECTIVE -: Retinoic acid (RA) is a ligand for nuclear receptors that modulate gene transcription and cell differentiation. Whether RA controls ectopic calcification in humans is unknown. We tested the hypothesis that RA regulates osteogenic differentiation of human arterial smooth muscle cells (SMC) and aortic valvular interstitial cells (VIC) that participate respectively in atherosclerosis and heart valve disease. APPROACH AND RESULTS -: Human cardiovascular tissue contains immunoreactive retinoic acid receptor (RAR), a retinoid-activated nuclear receptor directing multiple transcriptional programs. RA stimulation suppressed primary human cardiovascular cell calcification while treatment with the RAR inhibitor AGN 193109 or RARα siRNA increased calcification. RA attenuated calcification in a coordinated manner – increasing levels of the calcification inhibitor matrix Gla protein while decreasing calcification-promoting tissue non-specific alkaline phosphatase activity. Given that nuclear receptor action varies as a function of distinct ligand structures, we compared calcification responses to cyclic retinoids and the acyclic retinoid, peretinoin. Peretinoin suppressed human cardiovascular cell calcification without inducing either secretion of apolipoprotein-CIII, which promotes atherogenesis, or reducing cytochrome P450 family 7 subfamily A member 1 expression, which occurred with cyclic retinoids all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid. Additionally, peretinoin did not suppress human femur osteoblast mineralization, whereas all-trans retinoic acid inhibited osteoblast mineralization. CONCLUSIONS -: These results establish retinoid regulation of human cardiovascular calcification, provide new insight into mechanisms involved in these responses, and suggest selective retinoid modulators, like acyclic retinoids may allow for treating cardiovascular calcification without the adverse effects associated with cyclic retinoids.