Background: TM6SF2 and NCAN are genes known to be related to fibrosis and steatosis but are not thoroughly investigated in the case of chronic Hepatitis C (HCV) in Egyptians.  Aim: This study is carried to investigate the role of TM6SF2 and NCAN in chronic HCV Egyptian patients. Methods: This retrospective study was carried out on 165 patients with chronic HCV who received treatment for it. Results: TM6SF2 showed statistical significance with viral load with a p-value of 0.02 but no statistical significance with fibrosis or activity. NCAN showed statistical significance with activity with a p-value of 0.011. Conclusion: this is the first work recording the prevalence of TM6SF2 (rs58542926) and NCAN (rs2228603) polymorphism in upper African HCV patients. TM6SF2 is not associated with fibrosis or activity in Egyptian patients infected with chronic hepatitis C but associated with high viral load. On the other side, NCAN is associated with severity of activity in the same studied group but no relation with the viral load. These results explain their additive effect exerted during HCV infection which should be further extensively studied.