Objectives: Elevated levels of C-reactive protein are one of the strongest prognostic factors in atherosclerosis. In addition to predicting vascular disease, C-reactive protein may directly facilitate the development of a proinflammatory and proatherosclerotic phenotype. Recent studies have demonstrated marked up-regulation of various adhesion molecules and inflammatory responses in endothelial cells subjected to C-reactive protein. The nuclear factor-κB signal transduction is known to play a key role in the expression of these proatherogenic entities. This study examines the direct effects of C-reactive protein on nuclear factor-κB activation and related mechanisms in saphenous vein endothelial cells. Methods: The activation of nuclear factor-κB was determined by confocal microscopy assessing the nuclear localization of nuclear factor-κB in endothelial cells incubated with C-reactive protein (50 μg/mL) for 30 minutes and 3 hours. Cells not incubated with C-reactive protein were used as negative controls, and cells incubated with tumor necrosis factor-α (10 ng/mL) for 15 minutes were used as positive controls in all studies. The degradation of IκB-α and IκB-β was assessed by Western blotting of the cell lysates obtained from cells incubated with human recombinant C-reactive protein (50 μg/mL) for 15 minutes, 30 minutes, and 1 hour. Results: Nuclear factor-κB nuclear translocation in endothelial cells increased significantly after 30 minutes of incubation with C-reactive protein (P < .01). Nuclear localization of nuclear factor-κB returned to baseline levels after 3 hours of incubation with C-reactive protein. Incubation with C-reactive protein resulted in degradation of IκB-α that was maximal at 30 minutes (P < .05). C-reactive protein showed no significant effect on IκB-β degradation. Conclusions: These data demonstrate, for the first time, that C-reactive protein activates the nuclear, factor-κB signal transduction pathway in endothelial cells. Degradation of IκB-α, but not IκB-β, seems to be the major pathway leading to nuclear factor-κB nuclear translocation and activation induced by C-reactive protein. These data support the concept that C-reactive protein, at concentrations known to predict diverse vascular insults, directly facilitates a proinflammatory and proatherosclerotic phenotype through activation of nuclear factor-κB. These data have important implications for saphenous vein atherosclerosis in patients with elevated C-reactive protein levels.