A large body of evidence points to oxidative stress as an important trigger in the complex chain of events leading to atherosclerosis. Reactive oxygen species have also been implicated in the pathophysiology of restenosis after percutaneous coronary interventions (PCI). The powerful antioxidant probucol has been shown to prevent coronary restenosis after balloon angioplasty in the MultiVitamins and Probucol (MVP) trial and other clinical studies. Probucol has also induced regression of carotid atherosclerosis in the Fukuoka Atherosclerosis Trial (FAST). However, prolongation of the QT interval with probucol remains a long-term safety concern. AGI-1067, a metabolically stable analog of probucol, is a vascular protectant (V-protectant) with strong antioxidant properties, equipotent to those of probucol. This V-protectant has been effective at preventing atherosclerosis in all tested animal models, including the low-density lipoprotein receptor–deficient and apolipoprotein E–knockout mice and the hypercholesterolemic primate. AGI-1067 improved luminal dimensions of the PCI site and reduced restenosis in the Canadian Antioxidant Restenosis Trial (CART-1). In contrast to probucol, AGI-1067 did not induce prolongation of the QT interval. AGI-1067 also improved luminal dimensions of the reference segments in the PCI vessels in CART-1, an effect that suggests a direct antiatherosclerosis effect. This has potentially important implications, as local approaches to prevent restenosis, such as coated stents, are not expected to prevent atherosclerosis progression, myocardial infarction, and cardiovascular death. Considering that oxidative stress and inflammation may persist for a prolonged period after stenting, treatment with AGI-1067 for the entire period of risk after PCI (instead of only 4 weeks in CART-1) may result in enhanced protection against luminal renarrowing in the ongoing multicenter CART-2 trial. Because the ultimate goal of therapy for patients with coronary artery disease must remain prevention of disease progression and atherosclerosis-related events, CART-2 will test the value of AGI-1067 for the reduction of both post-PCI restenosis and atherosclerosis progression.