Background: There is a suggestion that increased aortic stiffness can be the early manifestations of the atherosclerosis process and is related to decrease coronary flow after coronary stenting. We aimed to evaluate whether aortic stiffness could predict occurrence of in-stent restenosis (ISR) and its relation to coronary flow reserve (CFR) after coronary artery stenting. Methods and Results: The study population included 126 patients with single vessel coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) with bare-metal stenting and at least 12 months of follow-up. All patients underwent noninvasive aortic stiffness index (ASI) assessment before stenting and coronary flow assessment 1 month after stenting. Clinical ISR was observed in 29 (23%) patients, whereas 97 patients remained free of signs or symptoms of recurrent ischemia. ASI was significantly higher in patients with coronary artery disease versus control subjects, and it is significantly increased in patients with restenosis versus those without restenosis (P < 0.0001 and P < 0.001, respectively). There was a significant negative correlation between ASI and CFR (P = 0.0001). The ASI was significantly correlated with C-reactive protein (r = 0.395, P < 0.03). On univariate and multivariate analysis, ASI was the strongest predictor of restenosis (OR 6.8, 95% CI 2.6–13.5). Conclusions: Increased aortic stiffness was an independent predictor of post stenting impaired coronary flow and occurrence of ISR in patients undergoing PCI. Evaluation of aortic stiffness may represent a useful screening tool to stratify patients according to future risk of restenosis.