Background: Early diagnosis of hepatocellular carcinoma (HCC) is the most important step in successfultreatment. However, it is usually rare due to the lack of a highly sensitive specific biomarker so that the HCCis usually fatal within few months after diagnosis. The aim of this work was to study the role of plasma nuclearfactor kappa B (NF-ĸB) and serum peroxiredoxin 3 (PRDX3) as diagnostic biomarkers for early detection ofHCC in a high-risk population. Materials and Methods: Plasma nuclear factor kappa B level (NF-ĸB) and serumperoxiredoxin 3 (PRDX3) levels were measured using enzyme linked immunosorbent assay (ELISA), in additionto alpha-fetoprotein (AFP) in 72 cirrhotic patients, 64 patients with HCC and 29 healthy controls. Results:NF-ĸB and PRDX3 were significantly elevated in the HCC group in relation to the others. Higher area undercurve (AUC) of 0.854 (for PRDX3) and 0.825 (for NF-ĸB) with sensitivity of 86.3% and 84.4% and specificity of75.8% and 75.4% respectively, were found compared to AUC of alpha-fetoprotein (AFP) (0.65) with sensitivityof 72.4% and specificity of 64.3%. Conclusions: NF-ĸB and PRDX3 may serve as early and sensitive biomarkersfor early detection of HCC facilitating improved management. The role of nuclear factor kappa B (NF-ĸB) asa target for treatment of liver fibrosis and HCC must be widely evaluated.