Several food items of plant origin, and in particular red wine, have been reported to protect from cardiovascular disease (CVD) development, thanks to their polyphenol components. Polyphenols undergo complex metabolic transformation during digestion and intestinal absorption. Here we report a novel model to study the effects of complex food matrices, applied to red wine, on gene expression in cultured primary human endothelial cells that takes into account the polyphenol metabolic transformation. Red wine was administered to human volunteers acting as 'bio-reactors'. Serum (RWS) obtained after 40 min was utilized to enrich endothelial cell culture media. The expression of specific genes involved in cell adhesion (vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM) and monocytes chemoattractant protein (MCP-1)) and fibrinolysis (tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2)) was considered as a molecular marker of cell function and related to the effects of RWS. The gene expression profile determined by RWS incubation was significantly different from that observed after the addition of red wine. Data obtained by this approach indicate the importance of taking into account the complex metabolic transformation of polyphenols that occurs during absorption when studying their effect on human health.