Oxidative reactions caused by cigarette smoke (CS) chemicals have been shown to initiate crucial events in atherogenesis. However, physicians and scientists are confronted with the paradoxical situation that an antioxidative treatment of smokers improves acute smoking effects but hardly has any impact on long term outcome of cardiovascular diseases (CVD). In this review we make an attempt to explain this paradox. First, smoke-derived free radicals and oxidants are part of CS causing a pro-oxidative state in the circulatory system. Further, smoke chemicals down-regulate antioxidant defence enzymes that would counteract the oxidative burden by cigarette smoke. With the prolonged exposure to smoke, oxidation catalysing metals accumulate in the vessel wall and mediate local oxidation reactions. Therefore, pharmacological intervention relying on non-selective antioxidants often appears to be ineffective. Consequently a novel strategy for the prevention and treatment of CVD caused by smoking is suggest, relying on a combined application of antioxidants, substitution of factors important for physiological oxidant defence, and metal-detoxifying agents.