The effects of long-term administration of Cyclosporin A (CSA), an immunosuppressive agent, on submandibular glands of male albino rats were investigated. Sialochemistry studies revealed a reduction of pilocarpine-stimulated flow rates to 54% compared to the controls. Salivary Mg(2+) and K+ were elevated and a marked decrease in total protein concentration was observed. Light and electron microscopic features of treated glands show marked changes at tissue level. An irregular pattern of the nucleus, mitochondrial alterations, reduction in the number of secretory granules and their aggregation, disturbances of cytoplasmic organelles, and isometric vacuolation were among the most striking findings. Our results show that CSA causes marked functional and morphological alterations in rat submandibular glands, which may be due to the drug's direct effects on the tissue.