Tramadol is widely used as a pain reliever; stimulant and it may delay ejaculation. But chronic tramadol users have adverse side effects. Aim: To clarify the worst effect of tramadol hydrochloride on male fertility and its role in neurodegeneration disorders due to oxidative stress in spite of indeed its use as ejaculation delaying. Materials and methods: This experimental study was performed upon 30 adult wistar rats. They were purchased from the National Research Centre Cairo, Egypt. These rats were divided into three groups (n=10), Group I, rats received vehicle and served as normal control. Group II, rats received low dose of tramadol (20 mg/Kg body weight/ day). Group III, rats received high dose of tramadol (50 mg/Kg body weight/day) for 12 weeks. Results: The results illustrated that tramadol in both low and high doses ingestion lead to weight loss, elevated Nitric Oxide Synthase (NOS) expression and plasma peroxidation value (MDA) but reduced Glutathione (GSH) and Superoxide Dismutase (SOD) in plasma were significantly decreased. Furthermore, plasma Monoamine Oxidase (MAO) was increased leading to serotonin (5-HT) and dopamine decrease in brain tissues proteins (p˂0.001). Plasma Testosterone level, sperm content and sperm vitality were significantly decreased (p˂0.001). Furthermore, hematoxylin and eosin (H&E) stain of the brain tissues showed few purkinje cells and the cells of granular layer were widely separated in the rats of low dose of tramadol group, but there was shrunken purkinje cells, some cells had pykinotic nuclei and majority of the cells of granular layer were non-nucleated, few of them had pykinotic nuclei in the rats of high dose of tramadol when compared to normal brain tissues of normal control rats. Conclusion: Long term tramadol administration developed oxidative stress, neurodegenerative disorders and male infertility.