Background: The discovery of miRNAs circulating in the peripheral blood has opened new directions of research to identify new non-invasive markers for diagnosis of diseases. Aim: The aim of the study was to evaluate the expression levels of circulating plasma miRNAs (miRNA-21 & miRNA-122) in Egyptian patients with chronic uncomplicated and complicated HCV. Patients & Methods: This study was conducted on 60 Chronic HCV infected patients. Patients were divided into three groups (20 patients each): uncomplicated HCV, cirrhosis, and hepatocellular carcinoma (HCC). All patients were subjected to laboratory investigations including complete blood picture, liver function tests. Expression levels of miRNA-21 and -122 in plasma using RT-PCR were determined. Results: MiR-NA-21showed significant fold increase in chronic uncomplicated HCV while significant fold decrease in cirrhotic and HCC groups (P = 0.036). On the other hand, miRNA-122 showed significant fold elevation in both chronic uncomplicated and cirrhotic groups and significant fold decrease in HCC group (P = 0.005). ROC curve analysis for miRNA-122 yielded 68.4% sensitivity and 100% specificity for the differentiation of HCC patients from non-HCC at a cutoff 0.184. Neither miRNA-21 nor miR-NA-122 was a successful predictor for HCC diagnosis. Conclusion: MiRNA-122 can be used as novel non-invasive biomarker for monitoring HCV related disease progression.