The etiology of Inflammatory bowel diseases (IBD) is not yet completely understood but a complex interplay among genetic, immunological, and environmental factors is known to induce a deregulated synthesis of a variety of proinflammatory mediators, including cytokines, reactive oxygen species (ROS) and nitric oxide (•NO), resulting in a disruption of the epithelial barrier and excessive tissue injury. Several studies showed that the barrier dysfunction in IBD is mainly due to a specific downregulation of key tight junction (TJ) -associated proteins. Here, using a cellular model of intestinal inflammation consisting of cytokines-stimulated HT-29 colon epithelial cells, we show that a polyphenolic red wine extract (RWE) significantly increased the mRNA of key TJ proteins as occludin, claudin-5 and ZO-1, not only preventing their decrease under inflammatory conditions but also enhancing their expression levels above those observed in control cells. Also, RWE prevented the cytokines-induced increase of claudin-2 mRNA. Taken together, these results suggest that, under inflammatory stimuli, RWE is able to promote the barrier function by affecting TJ protein expression and could potentially be useful in the treatment/prevention of IBD.