Hepatitis c virus (HCV) is the major cause for chronic hepatitis, Sofosbuvir (SOF) is a primary treatment choice for HCV patients however it has many side effects, Grape seed extract (GSE) is a dietary supplement proven to consist of phenolic compounds leading to an antioxidant property.Aim of the study: This work has been focused on the possible effect of SOF on the tongue Papillae of male Albino rats and assessment of the probable protective role of GSE as an antioxidant.Materials & methods: adult male Albino rats were utilized in the work (n=30), receiving drugs orally as a single daily dose for 6 weeks. The animals were arbitrarily divided into three groups. Group Ⅰ (control group): Rats received distilled water only. Group Ⅱ (SOF group): Rats received 40 mg\kg\day of SOF dissolved in distilled water (8mg\ml) via gastric tube. Group Ⅲ (combination SOF& GSE group): Rats received SOF with the same concentration as mentioned before in combination with GSE at a dose of 200mg \kg\day dissolved in distilled water given via gastric tube. After 6 weeks, all animals were sacrificed by ketamine overdose; tongues were carefully dissected and prepared to be examined under light microscope using Hematoxylin and Eosin (H & E) and immunohistochemical staining using ki67, CD20.Results: SOF-treated group showed degenerative changes to the papillae including torn and detached keratin layer, numerous intracellular epithelial vacuolations, degenerative areas in the connective tissue with leucocytic infiltrations. Immunohistochemically and statistically, there was highly significant reduction in the ki67 count, and also decrease in CD20 area % in Gp Ⅱ papillae compared to Gp Ⅰ and Gp Ⅲ. The administration of GSE with SOF minimized these changes.Conclusions: SOF has been proved to induce degenerative changes in the tongue papillae and these changes can be attenuated by GSE when it is co-administered with it.