Objective: To explore the clinical application of serum GP73 in the diagnosis and progress of hepatocellular carcinoma (HCC)., Methods: Enzyme-linked immunosorbent assay was employed to quantitatively detect serum GP73 in 59 HCC patients, 23 cases of hepatitis B virus (HBV)-related cirrhosis and 33 normal controls. The relationship between GP73 and diagnosis as well as progress of HCC was examined., Results: Significant differences existed when serum GP73 was categorized by Child-Pugh class A and B (P < 0.01). There was no correlation between GP73 levels and other parameters including age, gender, BCLC staging, HBV infection, tumor size, extrahepatic metastasis and tumor numbers. The serum GP73 with a mean level of [127 (147) µg/L, M(QR)] in HCC patients was significantly higher than that in normal controls or those with HBV-liver cirrhosis (P < 0.01). Based on the ROC curve analysis, the cut-off value was 99 µg/L with 64.4% sensitivity and 96.4% specificity. The sensitivity of diagnosing HCC with GP73 plus AFP improved (P = 0.025) , but not in specificity.Serum GP73 and AFP did not change greatly in terms of response assessment in mRECIST from baseline to progressive disease (P = 0.959, P = 0.788).No correlation existed between baseline concentration of GP73 with AFP and time to progression (r = 0.119, P = 0.608; r = 0.142, P = 0.540) ., Conclusion: GP73 may become a potential serum marker for diagnosing HCC. And a combination of AFP yields better outcomes. The exact relationship between mRECIST and GP73 as well as AFP shall be proved by large-scale clinical trials.