Integrin ␣v␤6 is generally not expressed in adult epithelia but is induced in wound healing, cancer, and certain fibrotic disorders. Despite this generalized absence, we observed that ␣v␤6 integrin is constitutively expressed in the healthy junctional epithelium linking the gingiva to tooth enamel. Moreover, expression of ␣v␤6 integrin was down-regulated in human periodontal disease, a common medical condition causing tooth loss and also contributing to the development of cardiovascular diseases by increasing the total systemic inflammatory burden. Remarkably, integrin ␤6 knockout mice developed classic signs of spontaneous, chronic periodontal disease with characteristic inflammation, epithelial down-growth, pocket formation, and bone loss around the teeth. Integrin ␣v␤6 acts as a major activator of transforming growth factor-␤1 (TGF-␤1), a key anti-inflammatory regulator in the immune system. Co-expression of TGF-␤1 and ␣v␤6 integrin was observed in the healthy junctional epithelium. Moreover, an antibody that blocks ␣v␤6 integrin-mediated activation of TGF-␤1 initiated inflammatory periodontal disease in a rat model of gingival inflammation. Thus, ␣v␤6 integrin is constitutively expressed in the epithelium sealing the gingiva to the tooth and plays a central role in protection against inflammatory periodontal disease through activation of TGF-␤1. (Am J Pathol