Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a low survival rate. Screening of early HCC diagnosis is the greatest challenge & thus decrease HCC related morbidity & mortality. Golgi protein 73 (GP73), a resident Golgi type-II membrane protein, is often upregulated in hepatocytes in different liver diseases. The aim of the paper is to study the usefulness of serum GP73 as a biomarker of HCC and hepatitis C virus (HCV) related liver cirrhosis. This study was conducted on 90 individuals who attended the Gastroenterology and Hepatology unit, (Department of Internal Medicine, Al-Zharaa University Hospital, Al-Azhar university) & Theodor Bilharz research Institute. The patients are divided into three groups: Group I: included 30 patients with HCC on top of liver cirrhosis. Group II: included 30 HCV positive patients with cirrhosis. Group III (Control group): included 30 HCV positive patients without cirrhosis. Results: highly statistically significant increase in serum GP73 in group I and II in comparison to control group and statistically significant increase in group I in comparison to group II. Serum GP73 can be used to discriminate between group I and II at a cutoff level of > 14, with 86.7% sensitivity 93.3% specificity and area under curve = 0.954. Also, it used to discriminate between group I and III at a cutoff level of 6, with 100% sensitivity & 100% specificity with area under curve = 1.0. GP73 is superior to Alpha-Fetoprotein (AFP) in early detection & diagnosing HCC.