Background-Plasma C-reactive protein (CRP) concentration is a strong predictor of atherosclerosis. However, to date, there is no in vivo evidence that CRP is proatherogenic. Methods and Results-We studied the effect of human CRP transgene (tg) expression, under basal and turpentine-stimulated conditions, on atherosclerosis in apolipoprotein (apo) E-/- mice. Aortic atherosclerotic lesions in 29-week-old male mice were 48% larger (P<0.02) in turpentine-treated mice and 34% larger (P<0.05) in untreated CRPtg +/0/apoE-/- mice. Turpentine treatment per se did not affect the extent of atherosclerosis in CRP transgenic or nontransgenic apoE-/- mice. Transgenic mice exhibited lower plasma complement C3 but increased deposition of CRP and C3 in the lesions, which suggests that CRP stimulated activation of complement within the lesion. There was more intense and widespread vascular cell adhesion molecule-1 and collagen staining in the lesions of CRPtg+/0/apoE-/- mice than in CRPtg 0/0/apoE-/- littermates. Lesions of CRPtg +/0/apoE-/- mice contained increased angiotensin type 1 receptor (AT1-R) transcripts and displayed increased AT1-R immunostaining compared with those of CRPtg0/0/apoE-/- mice. There was no difference in blood pressure in the 2 types of mice, which indicates that the proatherogenic effect of CRP-associated AT1-R overexpression is local and not mediated by its hypertensive properties. Conclusions-Human CRP transgene expression causes accelerated aortic atherosclerosis in apoE-/- mice. CRP was detected in the lesion, which was associated with increased C3 deposition and increased AT1-R, vascular cell adhesion molecule-1, and collagen expression. These data document a proatherogenic role for CRP in vivo.