Egypt is experiencing an epidemic hepatocellular carcinoma (HCC) due to widespread of hepatitis C virus (HCV) transmission. Aim: To explore the expression level of microRNA-15a (miR-15a) and its target "c-Myb" in Egyptian HCV- related HCC patients. 20 newly diagnosed HCC cases of different stages, 20 chronic HCV cases, and 20 apparently healthy subjects acted as controls were tested for circulating miR-15a and c-Myb level in serum. Real-time PCR was performed to assess miR-15a expression level in serum of all samples along with liver function tests. ELISA technique was applied for quantification of AFP and c-Myb. miR-15a was upregulated with reduced expression level of its target “c-Myb" through progression to HCC. Receiver operating characteristic (ROC) curve study showed that the best cutoff value of miR-15a for HCC diagnosis was ≥0.49-fold change (FC) with a sensitivity of 61% and specificity of 89%, which surplus AFP at cut-off value of ≥200 ng/mL, with 50% sensitivity and 84% specificity, respectively. Increased expression level of miR-15a in HCC cases implicate its contribution to HCC growth and spread by at least affecting c-Myb pathway, and hence may be used as a diagnostic biomarker for early diagnosis of HCC.