The consumption of some flavonoid rich foods has been shown to induce improvements in several intermediate markers of cardiovascular risk. Citrus fruits constitute a food source rich in a particular class of flavonoids, that of flavanones. Based on recent epidemiological data as well as on a large number of pre-clinical studies, citrus flavanones may exhibit interesting cardioprotective properties. However clinical evidences accounting for a benefit in consuming dietary flavanones to improve some cardiovascular endpoints are still very scarce. The present clinical study aimed at 1) characterizing the specific role of naringin in the effect of a long-term consumption of grapefruit juice on vascular function in humans and 2) analyzing changes in PBMCs transcriptome profile induced by grapefruit naringin. 52 healthy post-menopausal women were enrolled in randomized, controlled, cross-over trial. For two periods of 6 months, subjects consumed 340ml/d of grapefruit juice (212mg naringenin-glycosides) or a iso-energetic control beverage mimicking the composition of the juice but without naringenin. The effects on endothelium-dependent vasoreactivity (assessed by FMD), arterial stiffness (assessed by PWV) and blood pressure as well as on conventional systemic biomarkers of CV risk factors were evaluated. Furthermore, a global gene expression profiles in peripheral blood mononuclear cells was performed using microarrays. We showed that grapefruit juice could protect from age-related arterial stiffening, the effect specifically related to the presence of naringenin in juice. Modulation of arterial stiffness could be an interesting target by which grapefruit juice exerts beneficial effect on vascular health. The PBMCs nutrigenomic analyses showed that naringenin regulates the expression of genes involved in inflammatory processes. Further analyses may shed light on the molecular mechanisms involved in vascular effects of grapefruit flavanones.