Abstract: Introduction: Salivary secretion is entirely mediated by nervous mechanisms, para-sympathetic and sympathetic nerves are in contact with acinar, ductal and myoepithelial cells and blood vessels. Salivary hypofunction or xerostomia is induced by suppression of impulse traffic from the salivary nuclei to salivary glands. it is most frequently secondary to medication consumption. The aim of this study: This study was designed to detect weather the xerogenic potency of chronic consumption of tramadol is related to its neural effect only or it is also related to structural changes of the parotid gland. Materials and Methods: 16 adult male albino rats weighing (200-250 gm) were divided into 3 groups; control group (4 rats) received distilled water, tramadol group (6 rats) received 40 mg\kg of tramadol for 20 and 30 days, and tramadol withdrawal group (6 rats) received 40 mg\kg of tramadol then tramadol was withdrawn for 20 and 30 days. Parotid gland was processed for H&E, toluidine blue stain and capsase-3 immuno-histochemical stain, also levels of malondialdehyde (MDA) were detected. Results: H&E sections showed disorganization and apoptosis in tramadol treated groups; after tramadol withdrawal the glands restored its normal architecture, mitotic and apoptotic activity were observed. Apoptotic findings were confirmed with the results of caspase-3 immuno-histochemical staining. Toluidine blue stain detected decreased amount of zymogen granules within the acinar cells of tramadol group which increased gradually after its withdrawal. Levels of MDA were increased in tramadol groups indicating increased level of oxidative stresses, after tramadol withdrawal MDA levels decreased again. Conclusion: Xerogenic potency of tramadol could be attributed to structural changes within the gland not only to its neural effect.