Objective: C-reactive protein (CRP) is a risk marker and a potential modulator of vascular disease. It remains unclear as to whether CRP modulates nitric oxide synthase (NOS) activity and nitric oxide (NO) metabolism. We studied the effect of CRP on NO metabolism in transgenic mice that express human CRP (CRPtg). Methods and Results: CRPtg and wildtype mice underwent controlled femoral artery wire injury. CRP serum levels in CRPtg at baseline, 6h and 24 h after injury were 12.4±9, 18.6±6.9 and 58.4±13 mg/L, respectively while undetectable in all time points in wildtypes. Endothelial NOS (eNOS) protein and mRNA expression were significantly suppressed in the injured arteries of CRPtg mice (n=5, p<0.05). Similar reduction in eNOS expression was observed in the distant lung and heart. NO release post injury was significantly lower in CRPtg as measured by nitrate and nitrite breakdown products with a concomitant suppression of cyclic GMP NO signaling post- injury. Conclusions: eNOS and NO expression following vascular injury are locally and systemically suppressed in mice that express human CRP. These in vivo observations support the hypothesis that CRP modulates NO metabolism and may have implications regarding the mechanisms by which CRP modulates vascular disease.