The C-reactive protein (CRP) is a strong predictor of cardiovascular events both in the general population and in patients with coronary artery disease. We aimed to evaluate whether in cultured human vascular smooth muscle cells (hVSMC) CRP modulates the synthesis and release of metalloproteinase-2 (MMP-2), which is deeply involved in plaque instabilization and vascular remodeling, and of the tissue inhibitor of metalloproteinase-2 (TIMP-2). Both in supernatants and in cell lysates of cultured hVSMC exposed to CRP (0-10 mg/L), we evaluated MMP-2 activity (gelatin zymography), MMP-2 and TIMP-2 protein synthesis (immunoblotting), MMP-2 and TIMP-2 mRNA expression (reverse transcription-polymerase chain reaction). CRP effects were also investigated after cell exposure to specific MEK inhibitor PD98059 (15-30 micromol/L) to evaluate the involvement of mitogen-activated protein kinase (MAPK). CRP upregulated MMP-2 mRNA expression. MMP-2 synthesis and activity were increased by 1-10 mg/L CRP starting from 8-hour incubation. The effect was prevented by exposure to PD98059. CRP did not modify TIMP-2 mRNA expression, protein synthesis, and secretion. CRP, at concentrations that predict cardiovascular events, upregulates MMP-2 mRNA expression and increases MMP-2 protein synthesis and release in hVSMC through mechanisms involving activation of MAPK pathway. These data indicate that CRP is not only a risk marker for vascular events, but it is also directly involved in the mechanisms leading to remodeling and instabilization of atherosclerotic plaque.