Background: Taste disturbance among tramadol abusers has been reported in the last few years. Aim: To assess the toxic effects of tramadol abuse on tongue structure including taste buds and reversibility of these changes on withdrawal. In addition, assess the effect of tramadol on Ki-67 as general marker for cellular proliferation. Methods: Forty-two adult male Sprague Dawley rats were divided into six groups: group I received normal saline, groups II and III received tramadol hydrochloride 40mg/kg for 20 and 30 days respectively orally, groups IV, V and VI received tramadol hydrochloride 40mg/kg for 30 days orally then received normal saline only for 10, 20, 30 days respectively. Rats were sacrificed and their tongues were dissected out. Results: On histological examination, the covering epithelium, fungiform and filiform papillae, taste buds and muscle layer were distorted in group II. In group III more damage occurred with complete disappearance of taste buds. On tramadol stoppage, gradual restoration of epithelium, papillae, taste buds and muscle fibers structure began in groups IV and V. In group VI, most histological features were restored but did not return to normal. Regarding Ki-67 immunostaining, the reaction area in tongue tissue increased with tramadol administration then began to decrease on its cessation but did not return to normal up to 30 days after withdrawal. Conclusion: Tramadol can disrupt the histological structure of the tongue tissue, destroy taste buds, and these changes are reversible on withdrawal. In addition, these toxic effects are not dependent on Ki-67 pathway.