Tramadol is one of a typical centrally acting opioids.It is indicated for management of moderate to sever pain. Now it is considered to be the most widely sold analgesic in the world and is registered and marketed in more than 100 countries. Objectives: A study was conducted to investigate the histopathological changes in rat brain and spinal cord with particular reference to formation of red neurons in response to long term administration of Tramadol in progressively increased doses. Material& Methods: Sixty adult male albino rats (160-180 g) were included and divided into three groups. Control group: (a) given normal saline (n=10) for three months ( b) given normal saline (n=10) for one month orally. Group I (n=20) received Tramadol orally at doses 1/10 LD50 , 1/5 LD50 and lastly four times the initial dose for the first second and third months respectively. Group II 1/10 LD50 (22.8mg/kg/day)for one month. All rats were scarified after 24 hours of the last dose at the end of each experimental period under ether anesthesia. Craniotomy and laminectomy was performed and intact brains and spinal cords were dissected and removed for histopathological studies. The presence of number of red neurons which are histological marker of apoptosis were investigated in frontal, parietal, temporal, Entorhial, pyriform occipital , hippocampal and spinal cord tissues. Results: There was significant decrease in weight of experimental animals in both groups in comparison to the control one. The number of small sized neurons were greater in group II than in group I. There was statistical difference regarding neuopil density and color staining among three groups. Neuopil was lighter in staining and less dense in groups I and II comparing to control(p≤0.002 and p≤0.001) using ANOVA test. Red neurons were found in group I and II higher than control. There were statistical difference between density of red neurons in group I and II and control (p 0.001). The highest number of red neurons was found in hippocampal region followed by occipital and frontal. The abnormalities occurred in the spinal cord tissue is less than those in the brain tissue. The only changes were found in the neuropil (fainter and less dense in group Iand II compared with control. Conclusions: