Whether diet specific epigenetic changes can also be detected in circulating blood leukocytes or contribute to disease progression is a hot research topic. The correlation of genome-wide data on DNA methylation and gene expression unveiled that methylation of promoter regions is frequently associated with transcriptional repression of genes being under control of this promoter. On the other hand it was also observed that this simple relation is not universally applicable but rather depends on genes, cell types, tissues and genetic variants. The majority of these findings are derived from in vitro experiments with cell cultures. However, data that directly link DNA methylation changes with alterations in gene expression in humans are scarce. A first randomized controlled clinical study recently reported that the controlled intake of a cocoa extract by humans at cardiovascular risk is able to affect both global DNA methylation of white blood cells, as well as the expression of individual genes involved in the regulation of DNA methylation. Whether transcriptional changes induced by the regular consumption of dietary polyphenols on a whole genome level can be related to changes of the methylome in white blood cells has yet not been investigated. Taken together, it can be hypothesized that dietary flavanols are able to modulate the expression of genes being associated with CVD pathomechanisms via changes in the DNA methylation pattern of these genes. The present study aimed at investigating the impact of an 8 weeks controlled dietary intervention with MOF in smokers, i.e. humans with an increased risk of CVD, on genome-wide changes in leukocytes’ gene expression and relate them to changes in DNA methylation. In animal models and in vitro studies, the potential beneficial effect of flavanols on the prevention of different diseases including cancer, neurodegenerative and cardiovascular diseases has been demonstrated. This effect seems to be related to their capacity to modulate the activity of different enzymes, cell signalling proteins and expression of genes and proteins. A recent metaanalysis has revealed that grape seed extract appears to significantly lower systolic blood pressure and heart rate, and we have recently shown that consumption of grape seedderived MOF presented an overall vascular health benefit. The potential mechanism of action underlying these effects in humans is still largely unknown. The capacity of polyphenols to modulate gene expression profiles in circulating blood cells in humans has been described in a few clinical trials. These nutrigenomics studies have shown that hesperidin, quercetin, resveratrol or isoflavones can modulate the expression of 560 to over 4000 genes suggesting that the health benefits of polyphenols in humans is probably dependent on their genomic effects.