Background and study aim: Hepatoma is the most common cancer worldwide, being regarded as the fifth of all malignancies. Mandating for a new, sensitive and specific markers for HCC are critically needed. Human paraoxonase-1 (PON-1), a Ca⁺² dependent esterase in the liver, with antioxidant functions, and binds to the HDL particles and hence discarding carcinogenic lipid radicals as byproduct of lipid peroxidation. The aim of this study was to estimate the importance of serum PON-1 activity and concentration in HCC in Egyptian patients as a more sensitive and specific biomarker compared to an established biomarker; Alpha-fetoprotein (AFP). Patients and Methods: This study was conducted on 88 subjects: 64 patients; 40 patients with HCC, 24 cirrhotic patients and 24 healthy subjects who admitted in Internal Medicine Department, Suez CanalUniversityHospital, Ismailia, Egypt. Clinical and radiological investigations in those of the Cirrhotic, and HCC groups for viral hepatitis markers, liver function tests, serum assay of AFP and PON-1 activity and cconcentrations. Results: The results showed that PON-1 concentration was found significantly lower in HCC patients than those of the control and Cirrhotic group (p<0.001).The sensitivity and specificity of PON-1 concentration for HCC were superior to those of AFP and PON-1 activity especially in recently detected HCC. PON-1 concentration had a sensitivity of 88.3% and specificity of 90.48% at the optimal cut-off value of 70.55 (ng/ml). AFP gives a sensitivity of 82.50% and specificity of 73.08 at a cut-off 20.44 ng/ml. Conclusion: This study demonstrates that PON1 concentration and activity were superior to AFP in the recently detected HCC.