Radiation-induced xerostomia still represents a common symptom following radiotherapy of head and neck malignancies, which significantly impairs the patient's quality of life. In this cross-sectional study, human salivary glands were investigated to assess the role of Wnt/β-catenin and TGF-β pathways in the pathogenic process of radiogenic impairment of salivary function.Irradiated human salivary glands were investigated in patients with manifested xerostomia. Alteration of Wnt-1 and cell-cell adhesion was evaluated immunohistologically as well as changes in the expression of TGF-β were assessed in salivary gland tissue.We assessed two alteration patterns in which Wnt-1 expression represents one change along with up-regulation of β-catenin and E-cadherin in irradiated but viable acinar cells. Increased expression of tenascin-C was observed in sites of epithelial-mesenchymal interaction and loss of cell-cell adhesion was assessed in translocated epithelial cells in the stroma.Increased transdifferentiation and remodeling of acinar structures was associated with decrease of viable acinar structures. The role of Wnt and TGF signaling may provide a potential therapeutic approach to prevent radiation-induced damage to salivary glands during radiotherapy for head and neck cancer.