Background: Sodium valproate (SV) is a widely administered antiepileptic drug, although hepatotoxicity is a side effect.Vitamin E (vit. E) being a potent antioxidant agent and essential fat soluble nutrient that can dramatically decreased this hepatotoxic effect. Aim of the Work: To investigate the histopathological and ultrastructural changes caused by different doses of SV, observe their correlations with liver biomarker levels and assess the defensive role of vit. E against SV hepatotoxicity. Methods: Sixty male adult albino rats were randomly divided into six groups. Group 1 was treated with normal saline. Group 2 was treated orally with vit. E (100 mg/kg/day). Groups 3, 4 and 5 were treated intraperitoneally with SV at doses of 100, 300 and 500 mg/kg/day, respectively, for 8 consecutive days. Group 6 was treated intraperitoneally with SV (500 mg/kg/day) and orally with vit. E (100 mg/kg/day) for 8 consecutive days. On the ninth day, blood samples were collected to assess the biochemical markers of the liver, and the results were statistically analyzed. The rats were deeply anaesthetized and sacrificed. Liver specimens were carefully dissected, and portions were fixed in 10% formalin solution for histopathological examination; others were fixed in 2.5% glutaraldehyde for ultrastructural study. Results: The liver function among the different groups was found to be significantly changed in dose dependent manner. Histopathological examination showed gradual distortion of hepatic lobular architecture and infiltration of lymphocytic cells. Concerning hepatocyte ultrastructure, SV was a destructive compound for most intracellular organelles. This toxicity was most obvious in the groups treated with higher doses; however, concurrent administration of vit. E with SV provided some hepatoprotection. Conclusion: SV is a destructive compound to the liver architecture, especially in high doses. However, SV damage can be attenuated by concurrent administration of vit. E, which considerably decreases most SV-induced hepatotoxicity.