C-reactive protein (CRP) is a risk factor for cardiovascular events and functions to amplify vascular inflammation through promoting endothelial dysfunction. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) is the primary endothelial receptor for oxLDL and both its expression and function are associated with vascular inflammation. As a scavenger receptor, LOX-1 is capable of binding to a variety of structurally unrelated ligands. Evidence is provided that demonstrates that CRP can act as a novel ligand for LOX-1. The direct interaction between these two proteins was demonstrated with purified protein in both ELISA and alphascreen assays. This interaction could be disrupted with known LOX-1 ligands, such as oxLDL and carrageenan. Moreover, the CRP interaction with cell surface expressed LOX-1 was confirmed in cell-based immunofluorescent binding studies. Mutagenesis studies demonstrated that the arginine residues forming the basic spine structure on the LOX-1 ligand binding interface were dispensable for CRP binding, suggesting a novel ligand binding mechanism for LOX-1 distinct from that used for oxLDL binding. Treatment of human endothelial cells with CRP led to activation of pro-inflammatory genes including IL-8, ICAM-1 and VCAM-1. The inductions of these genes by CRP were LOX-1 dependent as demonstrated by their attenuation in cells transfected with LOX-1 siRNA. Our study identifies and characterizes the direct interaction between LOX-1 and CRP and suggests that this interaction may mediate CRP-induced endothelial dysfunction.