To investigate the expression profiles of serum Golgi protein-73 (GP73) in liver cirrhosis and primary hepatic carcinoma (PHC) and determine its clinical value for differential diagnosis. Serum protein expressions of GP73 and alpha-fetoprotein (AFP) were detected by enzyme-linked immunosorbent assay and chemiluminescence assay, respectively, in patients with PHC (n=80), liver cirrhosis (n=65), and healthy controls (n=50). Inter-group changes were assessed by Kruskal-Wallis test, and significance of these differences was assessed by Mann-Whitney test. A receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic efficiency and determine the cut-off values for GP73 and AFP. Sensitivity and specificity were compared by the Chi-squared test. Correlation between serum GP73 expression and clinical parameters was determined by Spearman's rank correlation analysis. The PHC group showed significantly higher serum GP73 (282.0 mug/L) than the liver cirrhosis group (211.8 mug/L) and control group (58.3 mug/L) (H = 93.30, P less than 0.01). For differential diagnosis of PHC and liver cirrhosis, the cut-off value was 318.1 mug/L for GP73 and 13.4 mug/L for AFP. Sensitivity of GP73 was lower than AFP (45% (36/80) vs. 65% (52/80); X2 = 8.02, P less than 0.05). Specificity of GP73 was lower than AFP but no significance was found (83.1% (54/65) vs. 87.7% (57/65); X2=0.27, P more than 0.05). The areas under the ROC curves were not significantly different between GP73 and AFP (0.65 (95% confidence interval (CI): 0.54~0.72) vs. 0.75 (95% CI: 0.67~0.83); Z = 1.88, P more than 0.05). The area under the ROC curves increased but not significantly (0.80 (95% CI: 0.73~0.88) vs. 0.75 (95% CI: 0.67~0.83); Z=2.61, P more than 0.05). Serum GP73 was correlated with liver cirrhosis (r=0.27), vascular invasion (r=0.29), and TNM staging (r=0.27) (all P less than 0.05), but not with sex (r=0.13), age (r=0.10), enhanced AFP (> 13.4 mug/L; r=0.03), tumor size (r=0.18), or distant metastasis (r=0.04), all P less than 0.05. Serum GP73 and AFP have comparable diagnostic efficiency, but the sensitivity of AFP is superior for differential diagnosis of liver cirrhosis and primary hepatic carcinoma. Elevated serum GP73 may be correlated with liver tumor load and aggressiveness.