The purpose of the current study was to investigate the possibility of vitamin (Vit.) C and E in protecting rat epididymis from MSG-induced histological changes. Twenty-five adult male albino rats divided into five groups (n=5): control, MSG; MSG+Vit.C.; MSG+Vit.E. and MSG +Vit. C+Vit. E. This treatment lasted for forty days. The histological examinations include use of H&E stain and Masson trichrome and histochemical (Periodic Acid Schiff reaction (PAS)). The present results showed that, all groups' B.W. after treatment was significantly higher than that before treatment. However, after treatment, MSG, and MSG+Vit. E caused a high significant decrease in B.W., respectively. There were no appreciable variations in the epididymis weight between the groups MSG+Vit. E and MSG+Vit. C+Vit. E. Histological investigations, indicated none of the treated groups significantly altered the bulk of the epididymis tissues, except for some histological alteration; however, the MSG+Vit.C+Vit.E group showed few effects. These alterations include blood vessel congestion, inflammatory cell infiltration, giant cell formation, expansion of interstitial spaces, hyperplasia and vacuolation of epithelial tubule lining, and hydropic degeneration. MSG show marked deposition of collagen fibers in the capsule, epididymal tubules, interstitial space and basal lamina. While remaining groups indicated the presence of the moderate amount of collagen fibers. Basal lamina and interstitial cells in groups of the MSG; MSG+Vit.C. and MSG+Vit.E. ; exhibited a strong PAS response. Whereas, the MSG+ Vit.C+ Vit.E group had moderate PAS reaction. In conclusion, combining Vit. C and Vit. E with MSG may lessen its toxicity. It is imperative to reevaluate the use of MSG as a flavor enhancer.