Reactive oxygen species (ROS) is excessively generated during tumor development yielding the oxidatively modified products of proteins and DNA. These DNA alterations could contribute to the development of cancer through the activation of oncogenes and inactivating tumor suppressor genes (TSGs). Therefore, 8-OHdG DNA oxidative damage and TP53 protein expression were evaluated amongst HCV-Chronic liver disease patients to explore their possible role in hepatocarcinogenesis and to predict HCC development at early stages. A total of 141 patients with HCV-related liver diseases; 69 with hepatocellular carcinoma and 72 with liver cirrhosis were enrolled in this study in addition to 56 healthy subjects.Serum 8-OHdG and TP53 expression by ELISA were markedly elevated in HCC patients compared to LC and healthy individuals (p < 0.0001). A significant correlation was noted for 8-OHdG and TP53 with disease progression and tumor differentiation but not with tumor site. 8-OHdG and TP53 were highly (p < 0.05) predicting for HCC at early stages and the diagnostic performance for discriminating HCC from LC by ROC curve showed the best AUC was recorded for 8-OHdG (0.745) followed by TP53 (0.667) with accuracy (87.2% and 82% respectively). Therefore, HCV-induced oxidative DNA damage could increase the carcinogenic potential of HCC development through the activation of TP53.