Background— Inflammation plays a crucial role in atherosclerosis. An elevated serum C-reactive protein (CRP) level is a strong marker for future atherosclerotic cardiovascular diseases. In addition, recent data suggest that CRP may directly promote atherogenesis. In this study, we investigated whether CRP can directly activate human circulating monocytes. Methods and Results— Incubation of THP-1 monocytes with CRP (10 μg/mL) increased CC chemokine receptor 2 (CCR2) expression at both the protein and transcript levels, which in turn enhanced chemotaxis mediated by monocyte chemoattractant protein-1 (MCP-1) up to 2-fold. The CRP-induced upregulation of CCR2 expression involved binding of CRP to the FcγR, most notably FcγRI, and phospholipase D1 activation. Serum high-sensitivity CRP levels in 52 normocholesterolemic human subjects were positively correlated with CCR2 surface expression on circulating monocytes ( r =0.62, P <0.001) and MCP-1–mediated monocyte chemotaxis ( r =0.53, P <0.001). Conclusions— Elevated blood CRP levels may promote accumulation of monocytes in the atherogenic arterial wall by increasing chemotactic activities of monocytes in response to MCP-1.