Selenium (Se) is an essential trace element, functioning within a distinctive set of proteins in the form of the 21st amino acid, selenocysteine (Sec). Se deficiency leads to decreased incorporation of Sec into selenoproteins, often culminating in pathological conditions. Se supplementation has demonstrated positive health outcomes, underscoring the health benefits of Se. There are twenty-four selenoproteins in mice (25 in human). Selenoprotein W (selenoW) is the smallest selenoprotein that is expressed in various tissues and is highly sensitive to dietary Se intake. SelenoW is reported to regulate cell cycle progression, cellular protection against redox stress, and regulation of immune cell functions although the mechanistic details are unknown. Previous research in our lab has shown whole body selenoW knock out (KO) mice have increased disease severeness upon 4% dextran sulfate sodium (DSS)-induced colitis, with increased inflammation and colonic tissue damage. SelenoW KO mice colon had reduced Yap1 and Egfr expression indicating impairment of epithelial cell regeneration. To study the specific role of selenoW in epithelial cells upon DSS administration, we generated epithelial-specific SelenoW KO mice (SelenoWfl/fl villin cre+/-) that were subjected to 4% DSS water for 5 days followed by 4 days recovery phase with regular drinking water. SelenoWfl/fl villin cre+/- mice showed increased colitis severity, with increased weight loss and reduced colon length. qPCR analysis with colon samples showed upregulation of proinflammatory cytokine Il1 and Tnf expression, while decreased anti-inflammatory and pro-resolving cytokine Il10 expression in the SelenoWfl/fl villin cre+/- mice, compared to WT. These results together with our previous finding suggest that the lack of selenoW expression in epithelial cells results in increased inflammation, impaired epithelial regeneration, delayed recovery, and increased disease severity. The protective role of SelenoW in colitis provides a new therapeutic target for treating inflammatory bowel disease, particularly ulcerative colitis.