The purpose of this study was to evaluate the effect of repeated tramadol drug administration on some biochemical and immunological parameters in rats. One hundred male albino rats were divided into three main groups. Group I (control): contains twenty rats administered saline solution. Group II (therapeutic dose group): forty rats received a daily oral dose of tramadol Hcl suspended in saline solution equal to 22.5 mg/kg/day for nine weeks. Ten rats of second group were left two weeks more without any additional treatment as a recovery period. Group III (over dose group): 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, second and third three weeks of the study, respectively for nine weeks. Ten rats of third group were left for two weeks more without any additional treatment as a recovery period. The obtained results showed significant increase in serum marker (Urea, creatinine, sialic acid, TNF-α and IL-1β) levels, and brain tissue (NF-KB and MPO) levels in both tramadol therapeutic and overdose groups towards its normal ranges. However, brain tissue antioxidant parameters (GPX and GSH) levels and liver tissue marker cyp2E1were markedly decreased. These results showed that, chronic tramadol administration induced kidney dysfunction, brain injury, oxidative and inflammatory stress in rats as well as degenerating endogenous antioxidant defense system mechanisms. These findings are of importance to be considered in the patients who use tramadol as a pain killer especially in the long term condition.