Atherosclerotic vascular dysfunction is a chronic inflammatory process that spreads from the fatty streak and foam cells through lesion progression. Therefore, its early diagnosis and prevention is unfeasible. Reactive oxygen species (ROS) play important roles in the pathogenesis of atherosclerotic vascular disease. Intracellular redox status is tightly regulated by oxidant and antioxidant systems. Imbalance in these systems causes oxidative or reductive stress which triggers cellular damage or aberrant signaling, and leads to dysregulation. Paradoxically, large clinical trials have shown that non-specific ROS scavenging by antioxidant vitamins is ineffective or sometimes harmful. ROS production can be locally regulated by cellular antioxidant enzymes, such as superoxide dismutases, catalase, glutathione peroxidases and peroxiredoxins. Therapeutic approach targeting these antioxidant enzymes might prove beneficial for prevention of ROS-related atherosclerotic vascular disease. Conversely, the development of specific antioxidant enzyme-mimetics could contribute to the clinical effectiveness.