Background:  Due to the high frequency of HCC, ongoing research is needed to find precise, non-invasive biomarkers for early identification and follow-up that will improve prognostic results. Patients and methods: this study was conducted on 90 patients with liver diseases and 25 healthy control G1, patients divided into 4 groups, (G2) 25 patients with HCV infection, (G3) 25 HCC+HCV infection, (G4) 25 patients with HBV infection, (G5) 15 patients with HCC + HBV. Results: Serum miR-122 and TNF-α levels were increased in HCV and HBV infection significantly with p-value >0.001^*compared to the control group, and their levels decreased when developed into HCC but still higher than the healthy subjects significantly with p-value >0.001. For discriminating HCV from HCV+HCC the cut-off for miR-122 was >7.1 at sensitivity 100%, specificity 100%, and the AUC was 1.0 (Excellent) P-value <0.001, also the sensitivity and specificity for TNF-α 72%, and 60% respectively with cut off >12.1 and AUC of 0.745 (Good) p-value 0.003. For discriminating HBV from HBV+HCC the cut-off for miR-122 was ≤6.4 at a sensitivity of 86.67% and specificity of 96%, and the AUC of miR-122 was 0.99 (Excellent) P-value <0.001, also the sensitivity and specificity for TNF-α 93.33%, and 48.0% respectively with cut-off ≤15.73, TNF-α has AUC of 0.527 (fair) it was not significant p-value 0.780.