The study investigates the vascular benefits of flavanol-rich cocoa, focusing on the role of (−)-epicatechin. Healthy male adults consumed high- and low-flavanol cocoa drinks, with the high-flavanol drink significantly increasing flow-mediated vasodilation (FMD), nitric oxide (NO) species levels, and microcirculation. Multivariate regression identified (−)-epicatechin and its metabolite, epicatechin-7-O-glucuronide, as key predictors of these vascular effects. Ex vivo experiments using rabbit aortic rings showed that a mixture of flavanols/metabolites mimicked acetylcholine-induced vasodilation, which was blocked by NO synthase (NOS) inhibition. Oral administration of pure (−)-epicatechin to humans also increased FMD and patency index, similar to the effects of flavanol-rich cocoa. Chronic consumption of high-flavanol diets was associated with increased urinary excretion of NO metabolites, suggesting enhanced NO production. The findings provide evidence that (−)-epicatechin mediates the vascular benefits observed with flavanol-rich cocoa consumption, supporting the epidemiological association between flavanol-rich diets and reduced cardiovascular risk.The study investigates the vascular benefits of flavanol-rich cocoa, focusing on the role of (−)-epicatechin. Healthy male adults consumed high- and low-flavanol cocoa drinks, with the high-flavanol drink significantly increasing flow-mediated vasodilation (FMD), nitric oxide (NO) species levels, and microcirculation. Multivariate regression identified (−)-epicatechin and its metabolite, epicatechin-7-O-glucuronide, as key predictors of these vascular effects. Ex vivo experiments using rabbit aortic rings showed that a mixture of flavanols/metabolites mimicked acetylcholine-induced vasodilation, which was blocked by NO synthase (NOS) inhibition. Oral administration of pure (−)-epicatechin to humans also increased FMD and patency index, similar to the effects of flavanol-rich cocoa. Chronic consumption of high-flavanol diets was associated with increased urinary excretion of NO metabolites, suggesting enhanced NO production. The findings provide evidence that (−)-epicatechin mediates the vascular benefits observed with flavanol-rich cocoa consumption, supporting the epidemiological association between flavanol-rich diets and reduced cardiovascular risk.