Although few epidemical studies have demonstrated that C-reactive protein (CRP) is related to insulin resistance, no study to date has examined the molecular mechanism. Here, we show that recombinant CRP attenuates insulin signaling through the regulation of Syk tyrosine kinase on small G-protein RhoA, JNK MAP kinase, insulin receptor substrate-1 (IRS-1), and endothelial nitric oxide synthase (eNOS) in vascular endothelial cells. Recombinant CRP suppressed insulin-induced NO production, inhibited the phosphorylation of Akt and eNOS, and stimulated the phosphorylation of IRS-1 at the Ser307 site in a dose-dependent manner. These events were blocked by treatment with an inhibitor of RhoA-association kinase (Rock) Y27632, or an inhibitor of jun N-terminal kinase (JNK) SP600125, or the transfection of dominant negative RhoA cDNA. Next, anti-CD64 (FcRI), but not anti-CD16 (FcRIIIa) or anti-CD32 (FcRII) antibody, partially blocked the recombinant CRP-induced phosphorylation of JNK and IRS-1, and restored to a certain extent the insulin-stimulated phosphorylation of Akt. Furthermore, we identified that recombinant CRP modulates the phosphorylation of Syk tyrosine kinase in endothelial cells. Piceatannol, an inhibitor of Syk tyrosine kinase, or infection of Syk siRNA blocked the recombinant CRP-induced RhoA activity and the phosphorylation of JNK and IRS-1. In addition, piceatannol also restrained CRP-induced endothelin-1 production. We conclude that recombinant CRP induces endothelial insulin resistance and dysfunction, and propose a new mechanism by which recombinant CRP induces the phosphorylation of JNK kinase and IRS-1 at the Ser307 site through a Syk tyrosine kinase and RhoA-activation signaling pathway.