ntroduction: Aspartame is a widely used artificial non-nutritive sweetener, which replaced sucrose in foods for enhancing flavor while reducing calories. It was confirmed that aspartame was a multipotential carcinogenic agent increases the risk of lymphoma and neurological tumors. Aim of the work: This work is aimed to evaluate the effect of aspartame on the structure of the sciatic nerve and the possible role of ozone therapy. Material and methods: The present study was carried out on 30 adult male wister albino rats divided into three groups: control (I), aspartame(II) and ozone and aspartame treated (III) groups. Group (II) received aspartame (250 mg/kg/d) dissolved in distilled water and administered by gastric tube for 3 months. Group (III) received aspartame as in Group II, then received an ozone dose of 1.1 mg/kg/d intraperitoneal (IP) for 30 days. Rats were anesthetized and sciatic nerves were processed for light, electron microscope, morphometric and Real time-PCR analysis. Results: The sciatic nerve of aspartame group showed loss of regular architecture, separation of myelin lamellae with splitting of myeline sheath. Schwann cells appeared with vacuolated cytoplasm and collagen fibrils could be seen in the endoneurium. Immunohistochemically, there was decrease in expression of myeline basic protein (MBP) in myeline sheath and decrease in axon/fiber ratio (g ratio) statistically. Apparent structural and histomorphological improvement were noticed in ozone group. Conclusion: Aspartame induced histopathological changes in sciatic nerve. Our data suggests that ozone therapy has an important role in sciatic nerve regeneration by increasing the expression of neurotrophic and angiogenic factors establishing more favorable environment for nerve regeneration