The purpose of this study was to evaluate the possible neurodegeneration and oxidative stress induced by tramadol administration in male rats. One hundred male albino rats were divided into three groups. Group I (normal control): consisted of twenty rats, administered saline solution. Group II (therapeutic dose gp): forty rats, received oral dose of tramadol HCl suspended in saline solution equivalent to 22.5 mg/kg/day for nine weeks; ten rats were left for further two weeks without any additional treatment as a recovery period. Group III (over- dose gp): forty rats, received oral dose of tramadol HCl suspended in saline solution at doses of 30, 60 and 90 mg/kg/day on the first, the second and the third three weeks of the study, respectively; ten rats were left from Group III for further two weeks without any additional treatment as a recovery period. The obtained results showed significant increase in serum liver marker enzyme (ALT and AST) activities, and brain tissue MDA, NO, DNA fragmentation, 8-OHdG and caspase-3 in both tramadol therapeutic and overdose groups. However, brain tissue antioxidant enzyme (SOD and CAT) activities were markedly decreased. Tramadol withdrawal for two weeks produced significant improvement of all previous parameters towards its normal ranges. These results proved that, tramadol administration for 9 weeks induced liver dysfunction and brain injury in rats, as well as a degenerating endogenous antioxidant defense system mechanism. These findings are of importance to be considered in patients who use tramadol as a pain killer, especially in the long term conditions.