Transforming growth factor-β (TGF-β) is a pleiotropic growth factor; its overexpression has been implicated in many diseases, making it a desirable target for therapeutic neutralization. In initial safety studies, mice were chronically treated (three times per week) with high doses (50 mg/kg) of a murine, pan-neutralizing, anti-TGF-β antibody. Nine weeks after the initiation of treatment, a subset of mice exhibited weight loss that was concurrent with decreased food intake. Histopathology revealed a unique, nonneoplastic cystic epithelial hyperplasia and tongue inflammation, as well as dental dysplasia and epithelial hyperplasia and inflammation of both the gingiva and esophagus. In an effort to determine the cause of this site-specific pathology, we examined TGF-β expression in these tissues and saliva under normal conditions. By immunostaining, we found higher expression levels of active TGF-β1 and TGF-β3 in normal tongue and esophageal submucosa compared with gut mucosal tissues, as well as detectable TGF-β1 in normal saliva by Western blot analysis. Interestingly, mast cells within the tongue, esophagus, and skin co-localized predominantly with the TGF-β1 expressed in these tissues. Our findings demonstrate a novel and restricted pathology in oral and esophageal tissues of mice chronically treated with anti-TGF-β that is associated with basal TGF-β expression in saliva and by mast cells within these tissues. These studies illustrate a previously unappreciated biological role of TGF-β in maintaining homeostasis within both oral and esophageal tissues.