Background: Screening of early hepatocellular carcinoma (HCC) diagnosis is the greatest challenge for hepatologists. Alpha-fetoprotein (AFP) is the most common non-invasive biomarker used in HCC diagnosis. Objectives and Aims: To make a comparison between the new biomarker Golgi protein 73 (GP73) versus the standard biomarker AFP in the diagnosis of HCC. Methods: Our study was a case-control study, and 60 patients were included in the study. They were divided into two groups: 1) HCC patients with either chronic HBV or HCV infection (n=30); and 2) non-HCC patients with HBV or HCV infection who had either chronic hepatitis or liver cirrhosis (n=30). In addition, 30 healthy volunteers were included as a control group. Patients were subjected to liver function tests, kidney function tests, serum Golgi protein 73 and AFP levels. Imaging diagnosis of HCC was done by computed tomography (CT) or magnetic resonance imaging (MRI) based on American Association for the Study of Liver Diseases (AASLD) practice guidelines. Results: Statistically significant differences between groups in terms of serum AFP (p<0.001) and GP73 (p<0.001) were found. Non-HCC patients (chronic hepatitis and liver cirrhosis) and HCC patients had significantly higher AFP and GP73 than the control group. In addition, patients with HCC had significantly higher AFP and GP73 than chronic hepatitis and cirrhotic patients. GP73 had higher diagnostic performance than AFP. At a cutoff value of ≥8.4 ng/mL, GP73 yielded a sensitivity of 86.7% and specificity of 89% for the discrimination between HCC and normal populations. Similarly, at a cutoff value of ≥8.45 ng/mL, GP73 yielded a sensitivity of 83.3% and specificity of 84% for the discrimination between HCC patients and non-HCC patients. On the other hand, AFP at a cutoff value of ≥2.4 ng/mL yielded a sensitivity of 75.4% and specificity of 90% for the discrimination between HCC and normal populations; and at a cutoff value of ≥20.85 ng/mL, AFP yielded a sensitivity of 72.2% and specificity of 86.2% for the discrimination between HCC and non-HCC patients. Conclusion: Golgi protein 73 is a promising and accurate biomarker for early detection of HCC.