The study demonstrates that (-)-epicatechin, a flavanol found in cocoa, mediates the beneficial vascular effects of flavanol-rich cocoa in humans. In healthy males, consuming flavanol-rich cocoa led to increased levels of nitric oxide (NO) species, enhanced flow-mediated vasodilation (FMD), and improved microcirculation. Analysis of circulating flavanol metabolites identified (-)-epicatechin and its metabolite, epicatechin-7-O-glucuronide, as independent predictors of vascular effects. A flavanol/metabolite mixture mimicked acetylcholine-induced relaxation in rabbit aortic rings, and these effects were abolished by inhibiting NO synthase. Oral administration of pure (-)-epicatechin closely emulated the vascular effects of flavanol-rich cocoa. Chronic consumption of a high-flavanol diet was associated with increased urinary excretion of NO metabolites, supporting the idea of prolonged NO synthesis. The study also examined Kuna Indians, finding higher urinary excretion of NO metabolites in island-dwellers compared to mainland residents, suggesting a link between high-flavanol diets and sustained NO production. The findings indicate that (-)-epicatechin is causally linked to the vascular benefits of flavanol-rich cocoa, providing a mechanistic basis for the epidemiological observation of an inverse association between plant-based diets and cardiovascular disease risk. The study highlights the importance of flavanols in improving vascular function through NO-mediated mechanisms and supports the potential of flavanol-rich foods in promoting cardiovascular health.The study demonstrates that (-)-epicatechin, a flavanol found in cocoa, mediates the beneficial vascular effects of flavanol-rich cocoa in humans. In healthy males, consuming flavanol-rich cocoa led to increased levels of nitric oxide (NO) species, enhanced flow-mediated vasodilation (FMD), and improved microcirculation. Analysis of circulating flavanol metabolites identified (-)-epicatechin and its metabolite, epicatechin-7-O-glucuronide, as independent predictors of vascular effects. A flavanol/metabolite mixture mimicked acetylcholine-induced relaxation in rabbit aortic rings, and these effects were abolished by inhibiting NO synthase. Oral administration of pure (-)-epicatechin closely emulated the vascular effects of flavanol-rich cocoa. Chronic consumption of a high-flavanol diet was associated with increased urinary excretion of NO metabolites, supporting the idea of prolonged NO synthesis. The study also examined Kuna Indians, finding higher urinary excretion of NO metabolites in island-dwellers compared to mainland residents, suggesting a link between high-flavanol diets and sustained NO production. The findings indicate that (-)-epicatechin is causally linked to the vascular benefits of flavanol-rich cocoa, providing a mechanistic basis for the epidemiological observation of an inverse association between plant-based diets and cardiovascular disease risk. The study highlights the importance of flavanols in improving vascular function through NO-mediated mechanisms and supports the potential of flavanol-rich foods in promoting cardiovascular health.