Clinical and epidemiologic studies reveal an association between vitamin D deficiency and increased risk of cardiovascular disease. Because vascular smooth muscle cell (VSMC)‐derived tissue factor (TF) is suggested to be critical for arterial thrombosis, we investigated whether the vitamin D molecules calcitriol and paricalcitol could reduce the expression of TF induced by the proinflammatory cytokine TNF‐α in human aortic VSMCs. We found that, compared with controls, incubation with TNF‐α increased TF expression and procoagulant activity in a NF‐κB‐dependent manner, as deduced from the increased nuclear translocation of nuclear factor κ‐light‐chain‐enhancer of activated B cells protein 65 (p65‐NF‐κB) and direct interaction of NF‐kB to the TF promoter. This was accompanied by the up‐regulation of TF signaling mediator protease‐activated receptor 2 (PAR‐2) expression and by the down‐regulation of vitamin D receptor expression in a miR‐346‐dependent way. However, addition of calcitriol or paricalcitol blunted the TNF‐α‐induced TF expression and activity (2.01 ± 0.24 and 1.32 ± 0.14 vs. 3.02 ± 0.39 pmol/mg protein, P < 0.05), which was associated with down‐regulation of NF‐kB signaling and PAR‐2 expression, as well as with restored levels of vitamin D receptor and enhanced expression of TF pathway inhibitor. Our data suggest that inflammation promotes a prothrombotic state through the up‐regulation of TF function in VSMCs and that the beneficial cardiovascular effects of vitamin D may be partially due to decreases in TF expression and its activity in VSMCs.—Martinez‐Moreno, J. M., Herencia, C., Montes de Oca, A., Muñoz‐Castañeda, J. R., Rodríguez‐Ortiz, M. E., Díaz‐Tocados, J. M., Peralbo‐Santaella, E., Camargo, A., Canalejo, A., Rodriguez, M., Velasco‐Gimena, F., Almaden, Y., Vitamin D modulates tissue factor and protease‐activated receptor 2 expression in vascular smooth muscle cells. FASEB J. 30, 1367–1376 (2016). www.fasebj.org