Cevimeline is a muscarinic agonist that promotes saliva secretion and is used to treat Sjögren's syndrome (SS), an autoimmune disorder in which the exocrine glands that produce saliva are destroyed. Cevimeline is thought to affect the composition of saliva in part by regulating the localization of aquaporins (AQPs). In this study, we investigated the effects of chronic Cevimeline administration in the salivary glands of SS mice on the immunohistochemical localization of aquaporin (AQP)-1, 3, 4, 5 and 8. We used Cevimeline-untreated SS mice, treated SS mice, discontinued SS mice and untreated normal mice. AQP-5 was found in the apical and lateral membranes of acinar cells in the parotid and submandibular glands of cevimeline-treated SS mice and untreated normal mice. Saliva secretion and AQP-5 localization were sustained in SS mice who were chronically administered Cevimeline and at four weeks after discontinuation. Unlike AQP-5, the localization of AQP-1, 3, 4 and 8 were not affected by Cevimeline administration. Our findings demonstrated that administration of Cevimeline maintains the proper localization of AQP-5 in the acinar cells of the salivary gland, which may promote salivation in chronically treated SS mice. Clinically, this suggests that chronic Cevimeline administration may be useful therapeutically for SS patients suffering from a decrease in saliva secretion by improving the disordered AQP-5 localization.