Background: The Egyptian health authorities consider hepatocellular carcinoma (HCC) as the most challenging health problem, where the number of HCC patients increased to two folds over a decade. Although the prognosis of patients with HCC is generally poor, the 5- year survival rate is >70% if patients are diagnosed at an early stage. Advanced molecular studies determined that “γ-synuclein" (SNCG) proved to be contributed in some cancers, and that microRNA-15a (miR-15a) directly targets SNCG. Objective: Our goal was to study the altered expression level of miR-15a and its target protein SNCG in chronic HCV (CHC)- related HCC among Egyptian patients. Subjects & Methods: 60 subjects were involved in this case-control study; 20 newly diagnosed HCC cases of different stages, 20 CHC, and 20 healthy controls. All of them were tested for circulating miR-15a using Real-time PCR technique and ELISA for the SNCG protein in serum. Results: upregulation in miR-15a expression level and reduced concentration of its target protein SNCG were demonstrated in serum of HCC patients than CHC group. miR-15a revealed ability to differentiate between presence of single and multiple focal lesions in HCC patients (Mean±SD= 0.40±0.10 vs 1.96±0.56), respectively. Efficacy to be used as a tumor marker was tested by ROC curve analysis, which showed that miR-15a was more accurate in diagnosing HCC among CHC group with sensitivity= 61% & specificity= 89% at cut-off value of ≥0.49 Fold Change, than the conventional tumor marker AFP (with 50% sensitivity and 84% specificity), respectively at cut off value ≥200 ng/mL. Conclusion: miR-15a has a role in pathogenesis through HCC, at least via SNCG, and it may represent a promising biomarker for early diagnosis of HCC in CHC population.