Hepatocellular carcinoma (HCC) is a major complication associated with hepatitis C viral infection (HCV). The epithelial-mesenchymal transition (EMT) is critical in HCC invasion and metastasis. Several microRNAs (miRNAs) have been linked to HCV-related HCC. This study aimed to evaluate the relation between miR-21, phosphatase, tensin homolog deleted on chromosome ten (PTEN), and E-Cadherin with a flashlight on their role in the EMT process in HCV infection at different stages. One hundred HCV-infected patients were studied, 75 had HCV-induced cirrhosis (classified into Child A, B, and C), and 25 had HCC. In parallel, 45 healthy volunteers were considered normal controls. Circulating miR-21was detected by quantitative Reverse Transcription Polymerase Chain Reaction (qRT–PCR).PTEN and E-cadherin serum levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA). A significant elevation in miR-21 was observed in HCC patients compared with control ones(P˂0.01). HCC patients had the lowest E-cadherins and PTEN (P<0.01) compared with cirrhotic and normal subjects. In HCC patients, PTEN was positively correlated with E-cadherin (r= 0.501; p<0.01).  On the other hand, a negative correlation between miR-21 and both E-cadherins (r= -0.455; p<0.01) and PTEN (r= -0.255; p<0.05) was observed. Accordingly, up-regulation of miR-21 in the tumor is an important step in HCV-positive cirrhotic hepatocarcinogenesis and might result in concomitant down-regulation of PTEN and E-cadherin in favor of tumor promotion. Our data might be the first study that correlates miR-21, PTEN, and E-cadherin in different stages of HCV infection (from cirrhosis to HCC).