Plasma C-reactive protein (CRP) concentration is a biomarker of systemic atherosclerosis and may also be associated with vein graft disease. It remains unclear if CRP is also an important modulator of biologic events in the vessel wall. We hypothesized that CRP influences vein graft healing by stimulating smooth muscle cells (SMCs) to undergo a phenotypic switch. Distribution of CRP was examined by immunohistochemistry in pre-bypass human saphenous veins (HSVs) (n=21) and failing vein grafts (n=18, 25-4400 days postop). Quiescent HSVSMCs were stimulated with human CRP (5-50µgm/L). SMC migration was assessed in modified Boyden chambers with platelet derived growth factor BB (PDGF-BB; 5-10 ng/mL) as the chemoattractant. SMC viability and proliferation were assessed by trypan blue exclusion and reduction of Alamar Blue substrate, respectively. Expression of PDGF ligand and receptor (PDGFR) genes was examined at RNA and protein levels after 24-72h of CRP exposure. CRP staining was present in 13 of 18 diseased vein grafts where it localized to the deep media and adventitia, but it was minimally detectable in most pre-bypass veins. SMCs pre-treated with CRP demonstrated a dose-dependent increase in migration to PDGF-BB (p=.02), which was inhibited by a PDGF neutralizing antibody. SMCs treated with CRP showed a dose-dependent increase in PDGFR- expression and phosphorylation after 24-48h. Exogenous CRP had no effect on SMC viability or proliferation. These data suggest that CRP is detectable within the wall of most diseased vein grafts, where it may exert local effects. Clinically relevant levels of CRP can stimulate SMC migration by a mechanism that may involve upregulation and activation of PDGFR-.