The effects of gentamicin, lithium and combination of these drugs on ultrastructural morphology of rat submandibular glands were studied. Daily intraperitoneal injection of 40 mg/kg of gentamicin which causes chronic salivary gland toxicity, led to a marked decrease in gland's dry weight and total protein concentration but did not affect DNA content. Electron micrograph (EM) of submandibular acinar cells showed electron dense, whorls of rough endoplasmic reticulum and swollen mitochondria. Chronic treatment by lithium also caused a significant decrease in gland's dry weight and total protein concentration. Contrary to gentamicin, lithium treatment caused a significant increase in gland's DNA content but did not cause hyperplasia or hypertrophy of the cells as indicated in EM. Lithium also caused swelling of rough endoplasmic reticulum of acinar cells, Concurrent treatment by lithium and gentamicin increased the total protein concentration up to those of control values. Combination therapy significantly decreased gland's dry weight when compared with those of gentamicin and lithium alone. EM also showed extended cellular changes including swollen, electron dense and whorls of rough endoplasmic reticulum. Lithium concentration was considerably increased in submandibular gland as a result of combination therapy. We also observed unexplainable alterations in rat submandibular gland induced by lithium and gentamicin alone or combination therapy that some of them could be due to interactions of these drugs with intracellular cAMP or phosphoinositides second messenger pathways.