Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by an activated mucosal immune system leading to impaired epithelial barrier function and tissue destruction with relapsing diarrhea. An important structural correlate of intestinal barrier function is represented by epithelial tight junctions (TJs). TJs are arranged in strands that are located in the apicolateral membrane of neighboring epithelial cells, linking cells together and thus determining paracellular permeability. The aim of the study was to analyze the influence of oligomeric proanthocyanidin (OPCs) newly extracted from Thai red grape seed, which were waste products from wine process on TJ barrier functions. Regulation of transcription was analyzed by reporter gene assay (luciferase activity). Expression of TJs proteins and mRNA was analyzed in western blots and quantitative RT-PCR, respectively. Transepithelial electrical resistance of TJs barrier was analyzed by TER assay. Reporter gene assay revealed a stimulatory effect of OPCs on claudin-4 transcription and mRNA expression. Parallel to transcriptional, OPCs induced a strong increase of the TJs protein claudin-4. TER values were increased in dose- and- time dependent manner when treated with nonlethal concentration of OPCs. The natural OPCs extract from Thai red grape seeds enhances barrier function via transcriptional expression regulation of the TJs protein claudin-4, which represents an important protective effect of this substance against barrier disturbance in intestinal inflammation.