Background: The seventh leading cause of mortality worldwide was assessed as viral hepatitis. Approximately, 50% of mortality attribute to HCV, primary led to liver cirrhosis and tumor. Recently developing of high effective oral DAAs provided opportunity to decreased HCV diseases load and their onward transmission. With the possibility of eradicating HCV, the 'Global Health Sector Strategy on Viral Hepatitis 2016-2021 has recently been formulated by the WHO to eradicate HCV as a public health concern by 2030.MicroRNAs are small noncoding regulatory RNAs and circulate in blood in cell-free stable forms. MiR-122 levels commonly decreased in hepatocellular carcinoma comparing to normal liver and low miR-122 levels associated by bad prognosis. Overexpression of miR-122 diminishes tumorigenic properties in HCC cell lines, signifying its function as tumor suppressor gene. Objective: to evaluate miR-122 level at end of HCV treatment by DAAs and compare the results with miR-122 level in HCC patients, to assess the risk of HCC after DAAs treatment. Patients and Methods: A prospective case control study held at Ain Shams University hospital. Forty participants were included and further divided into: Group A: (10) HCV -ve participants as control group, Group B: (10) HCV infected patients with HCC, Group C: (10) HCV infected patients (F1, F2) treated with sofosbuvir, daclatasvir +/-Ribavirin for 12 weeks Group D: (10) HCV infected patients (F3, F4) treated with sofosbuvir, daclatasvir +/-Ribavirin for 12 weeks. Results: Baseline MiR-122 level was significantly lower in HCC patients than chronic HCV patients and normal controls with cutoff value ≤0.26 showing 80% sensitivity and 70% specificity. MiR-122 was significantly reduced at end of HCV therapy with DAAs in (F3, F4) patients than those with early fibrosis stages (F1, F2). Conclusion: HCV treatment with DAAs leads to miRNA 122 reduction more in (F3, F4) patients than those with early fibrosis stages (F1, F2), which may be related to hepatocarcinogenesis.