A higher intake of foods rich in flavonoids such as quercetin can reduce the risk of cardiovascular disease. Enzymatically modified isoquercitrin (EMIQ®) has a bioavailability 17-fold higher than quercetin aglycone and has shown potential cardiovascular disease moderating effects in animal studies. The present study aimed to determine if acute ingestion of EMIQ® improves endothelial function, blood pressure, and cognitive function in human volunteers at risk of cardiovascular disease. Twenty-five participants (12 males, 13 females) with at least one cardiovascular disease risk factor completed this randomized, controlled, crossover study. In a random order, participants were given EMIQ® (2 mg aglycone equivalent)/kg body weight or placebo alongside a standard breakfast meal. Endothelial function, assessed by flow mediated dilatation (FMD) of the brachial artery was measured before and 1.5 hrs after intervention. Blood pressure (BP), arterial stiffness, cognitive function, BP during cognitive stress and measures of quercetin metabolites, oxidative stress and markers of nitric oxide (NO) production were assessed post-intervention. After adjustment for pre-treatment measurements and treatment order, EMIQ® treatment resulted in a significantly higher FMD response compared to the placebo [0.60%, 95% CI: 0.03, 1.17 (p=0.04)]. Plasma concentrations of quercetin metabolites were significantly higher (p<0.001) after EMIQ® treatment compared to the placebo. No changes in blood pressure, arterial stiffness, cognitive function, or biochemical parameters were observed. In this human intervention study, the acute administration of EMIQ® significantly increased circulating quercetin metabolites and improved endothelial function. Further clinical trials are required to assess whether health benefits are associated with long-term EMIQ® consumption.