Objective— We examined the impact of C-reactive protein (CRP) on vascular smooth muscle cell (VSMC) expression of tissue factor (TF) and TF pathway inhibitor (TFPI). Methods and Results— TF mRNA, protein, and activity levels were significantly higher in VSMCs isolated from CRP-transgenic (Tg) mice than from wild-type (WT) mice. TFPI expression was significantly downregulated in CRP-Tg versus WT VSMCs. Transfection of human VSMCs with CRP expression plasmid significantly increased TF expression and decreased TFPI expression. Gene silencing of Fcγ receptor IIIa (FcγRIIIa) blocked the effect of CRP on VSMC TF expression. CRP activated p44/42, but not p38 or JNK MAP kinase (MAPK), and the effect of CRP on TF expression was blocked by pharmacological inhibitor of p44/42, but not p38 or JNK MAPK. Reactive oxygen species (ROS) scavengers blocked CRP-induced upregulation of VSMC TF expression. In vivo analyses revealed significant increases in TF expression and decreases in TFPI expression in carotid arteries of CRP-Tg mice versus WT mice. Conclusion— CRP increases TF and decreases TFPI expression by VSMCs in vitro and in vivo. Induction of TF expression by CRP is mediated by FcγRIIIa, p44/42 MAPK, and ROS generation. These data offer important insights into the role of CRP in the pathogenesis of arterial thrombosis.