Objective. Transforming growth factor β (TGFβ) plays a key role in the onset and resolution of autoimmune diseases and chronic inflammation. The aim of this study was to delineate the precise function of TGFβ signaling in salivary gland inflammation. Methods. We impaired TGFβ signaling in mouse salivary glands by conditionally inactivating expression of TGFβ receptor type I (TGFβRI), either by using mouse mammary tumor virus-Cre mice or by delivering adenoviral vector containing Cre to mouse salivary glands via retrograde infusion of the cannulated main excretory ducts of submandibular glands. Results. TGFβRI-conditional knockout (TGFβRI-coko) mice were born normal; however, female TGFβRI-coko mice developed severe multifocal inflammation in salivary and mammary glands and in the heart. The inflammatory disorder affected normal growth and resulted in the death of the mice at ages 4-5 weeks. Interestingly, male TGFβRI-coko mice did not exhibit any signs of inflammation. The female TGFβRI-coko mice also showed an increase in Th1 proinflammatory cytokines in salivary glands and exhibited an up-regulation of peripheral T cells. In addition, these mice showed an atypical distribution of aquaporin 5 in their salivary glands, suggesting likely secretory impairment. Administration of an adenoviral vector encoding Cre recombinase into the salivary glands resulted in inflammatory foci only in the glands of female TGFβRI-loxP-flanked (floxed) mice (TGFβRI-f/f mice), but not in those of male and female wild-type mice or male TGFβRI-f/f mice. Conclusion. These results suggest that female mice are uniquely more susceptible to developing inflammatory disorders due to impaired TGFβ signaling in their salivary glands.