The submandibular glands of female non-obese diabetic (NOD) mice (22-26 weeks of age) were studied by light and electron microscopy. Mononuclear cells consisting mostly of lymphocytes were recognized in and among the acini and secretory ducts. Some parts of the secretory ducts and mucous acini surrounded by lymphocytes showed destructive changes. In the secretory ducts lymphocytes invaded the duct epithelial lining and the duct lumen was occluded by these cells. The duct epithelial cells in such lesions were extremely distorted and tonofilament bundles running in various directions were present in the cytoplasm. Lymphocytes were in close contact with the duct epithelial cells. In the mucous acini some acinar cells, which appeared to be compressed by the infiltrating lymphocytes, showed degenerative changes. Immunocytochemical study revealed that both T- and B-lymphocytes were involved, T-lymphocytes tending to occupy the center of the infiltrate, while B-lymphocytes occupied the periphery. Although autoantibody against duct epithelial cells was identified, damage to duct epithelial cells was not correlated with the presence of this antibody. The morphological changes in the submandibular gland of the NOD mouse are very similar to those reported in the salivary gland of patients with Sjögren's syndrome.