Dry eyes and dry mouth are clinical hallmarks of Sjögren's syndrome. We assessed the distribution of aquaporin-5 (AQP5) in lacrimal gland biopsy samples. Healthy controls and patients with Mikulicz's disease or non-Sjögren's syndrome dry eye had the expected apical distribution of AQP5 in lacrimal acinar cells. By contrast, cytoplasmic AQP5 was seen in patients with Sjögren's syndrome. Sodium channel and sodium-potassium ATPase distributions were normal in all groups. These findings show a selective defect in lacrimal gland AQP5 trafficking in Sjögren's syndrome that might contribute to decreased lacrimation and dry eye in these patients.