Human studies provide evidence for beneficial effects of polyphenol-rich foods on cardiovascular health. The antioxidant activity of polyphenols potentially explains these effects, but is the antioxidant activity a reliable predictor for these effects? An International Life Sciences Institute Europe working group addressed this question and explored the potential of antioxidant claims for polyphenols in relation to cardiovascular health by using the so-called Process for the Assessment of Scientific Support for Claims on Foods project criteria. In this process, analytical aspects of polyphenols, their occurrence in foods, dietary intake, and bioavailability were reviewed. Human studies on polyphenols and cardiovascular health were reviewed together with methods for biomarkers of oxidative damage and total antioxidant capacity (TAC). In retrospective studies, F2-isoprostanes and oxidized LDL, the most reliable biomarkers of lipid peroxidation, and measures for TAC showed the expected differences between cardiovascular disease patients and healthy controls, but prospective studies are lacking, and a causal relationship between these biomarkers and cardiovascular health could not be established. Therefore, the physiological relevance of a potential change in these biomarkers is unclear. We found limited evidence that some types of polyphenol-rich products modify these biomarkers in humans. A direct antioxidant effect of polyphenols in vivo is questionable, however, because concentrations in blood are low compared with other antioxidants and extensive metabolism following ingestion lowers their antioxidant activity. Therefore, the biological relevance of direct antioxidant effects of polyphenols for cardiovascular health could not be established. Overall, although some polyphenol-rich foods exert beneficial effects on some biomarkers of cardiovascular health, there is no evidence that this is caused by improvements in antioxidant function biomarkers (oxidative damage or antioxidant capacity).