Background and study aim :Hepatocellular carcinoma (HCC) is the fifth most common neoplasm in the world, and the third most common cause of cancer-related death. Golgi protein 73 is normally expressed in epithelial cells of many human tissues. GP73 expression is upregulated in hepatocytes, and in serum from patients with hepatitis and liver cirrhosis regardless the etiology. This work aimed to study the diagnostic role of serum Golgi protein 73level as a marker for HCC. Patients and Methods: This study was conducted on 48 patients with HCC on top of liver cirrhosis (GI), 20 patients with liver cirrhosis (GII), and 20 healthy controls (GIII). Patient and controls were subjected to careful medical history, full clinical examination and laboratory investigations including CBC, ESR, liver function tests, renal function tests, viral markers, serum AFP and Serum Golgi protein 73 by ELISA. Results: Serum GP73 showed highly significant increase (with P value <0.001) in HCC group X±SD (1765.92±747.99) in comparison with cirrhoticX±SD (772.45±73.84) and control X±SD (458.30±103.03) groups, also significantly increased in cirrhotic group in comparison with control group. There was significant increase in mean values of serum GP73 in patients with HCC associated with portal vein thrombosis or lymph node enlargement also there was significant positive correlationbetween GP73 and tumor size. In diagnosis of HCC, at cut off point 55 ng/ml, AFP had sensitivity 81.3% and specificity 70.0%, and Gp73 at cut off point 847.5 ng/l, the sensitivity was 93.8% and specificity 90.0%. With combined use of AFP and Gp73: the sensitivity of diagnosis of HCC increased to 95.8%. Conclusion: Significant increase in sensitivity, accuracy and negative predictive value with combined use of AFP and Gp73 than AFP alone in diagnosis of HCC.