Circulating miR-122 is commonly deregulated in liver fibrosis and hepatocellular carcinoma. Fibronection (FN) has been related to liver fibrosis in chronic liver disease. This study examined whether circulating levels of miR-122 regulates tumorigenesis in hepatocellular carcinoma by targeting Bcl-w. Also in this study we tried to examine whether circulating level of miR-122 and FN can be used as noninvasive markers for liver injury in Egyptian patients with chronic hepatitis C virus infection, in addition tried to explore the potential usefulness of serum miR-122 and FN as a diagnostic markers of HCV-related hepatocellular carcinoma (HCC). Out of 84 participants; 20 patients were HCV positive infected patients, 44 HCC patients infected with HCV, and 20 healthy volunteers were also included. We determined the expression of levels of miR-122 and Bcl-w in serum using (qRT-PCR). In addition, the level of plasma FN was measured quantitatively by (ELISA). Mean miR-122 expression levels were up-regulated in both patient groups compared to control group. Conversely, mean Bcl-w expression levels were down-regulated in both patients groups compared to control group. In addition, mean levels of plasma FN were significantly higher in Patient groups as compared to control group (p=<0.001). Furthermore, expression levels of miR-122 and FN were positively correlated with ALT, AST, ALP and fibrosis stage, and negatively correlated with prothrombin concentration and Albumin in both patient groups. By analyzing the diagnostic performance of the studied parameters among patient groups; the combined use of FN and miR-122 achieved (sensitivity 84 % and specificity 70%) for the differentiation of HCC from HCV patients and (sensitivity 81 % and specificity 77%) for the differentiation of patients with early fibrosis from those with significant fibrosis. Conclusion: This study shed light on the functions of miR-122 which may act as an endogenous apoptosis regulator and thus negatively regulates tumorigenesis. Also this study concluded that miR-122 and FN can be used as novel biomarkers for liver injury and may be used to discriminate patients with HCC from HCV.