Background: Glutathione peroxidase 1 gene (GPX1) is the most common isoform of GPX family .It remove the reactive oxygen species in a continuous process. Since the identification of a well-characterized functional polymorphism named Pro198Leu (C>T) in GPX1 gene, abundant studies have evaluated the association between Pro198Leu polymorphism and tumor risk in diverse population. The present study was planned to evaluate the presence of GPX1 (Pro198Leu) polymorphisms in Egyptian patients with chronic hepatitis C virus. Methods: Genomic DNA from peripheral blood leukocytes of 243 patients with chronic hepatitis C, 134 of whom were diagnosed as hepatocellular carcinoma (HCC)and 112 healthy controls were enrolledandgenotypedGPX1Pro198Leu polymorphism by polymerase chain reaction_restriction fragment length polymorphism (PCR-RFLP) method. Results: A significant difference in the frequencies of Pro/Pro (32.8%) , Pro/Leu (59.7%) and Leu/Leu (7.5%) genotypes in cancer cases and in controls (57.1%,42.9%,0% respectively) were found. The results also indicated that the distribution of the all genotypes (PP,PL,LL) were significantly different between the control and HCV group (P =0.000, 0.01,0.004 respectively).Conclusion: The results of this study suggested that GPX1 Pro198Leu polymorphism could be a risk factor for HCV,HCC Egyptian patients. However, largescale studies on the effect of this polymorphism are needed for conclusive understanding.