Background: Inflammation is considered to be a major initiator to angioplasty-induced vascular restenosis. Proinflammatory cytokines stimulate vascular smooth muscle cell (VSMC) migration and proliferation leading to neointimal hyperplasia. It has been reported that chronic caffeine use suppresses the production of proinflammatory cytokine TNF-α (tumor necrosis factor Alpha) and alters adenosine receptor expression in human neutrophils, indicating that caffeine may attenuate vascular injury-induced inflammation and subsequent neointimal hyperplasia. Our current study was designed to test the hypothesis that chronic caffeine treatment decreases vascular injury-induced neointimal hyperplasia by suppressing VSMC migration and proliferation. Methods and Results: The experiments were carried out using both in vivo (rat carotid artery injury model) and in vitro (VSMCs isolated from rat aorta) models. Male Sprague-Dawley rats that received chronic caffeine treatment (10 and 20 mg/kg per day, through oral gavage) showed a significant decrease in neointimal hyperplasia when compared to rats that received vehicle. To understand the underlying mechanisms, we tested if caffeine inhibits fetal bovine serum (FBS)-induced VSMC migration and proliferation. We found that caffeine substantially suppressed FBS-induced VSMC migration and proliferation. The attenuation of FBS-stimulated cell migration is dose dependent. Conclusion: Together, our results suggest that chronic treatment with high concentrations of caffeine attenuates vascular injury-induced neointimal hyperplasia by suppressing smooth muscle cell migration and proliferation in rats.