Objective The purpose of detecting the expression of serum AFP,AFP-L3, GPC3 and MMP2 was to study the diagnostic value of the combined detection of four indicators in HCC.Method 60 HCC patients,60 case of liver cirrhosis patients,60 cases of chronic viral hepatitis B ( HBV) patients and 60 healthy controls were selected from Outpatients in Public Health Clinical Center of Chengdu from December 2019 to December 2020.The serum AFP,AFP-L3 and GPC3,MMP2 detected with chemiluminescence and enzyme-linked immunosorbent double antibody sandwich method, respectively. Analyzed the differences of serum marker in each group, and the diagnostic efficiency of combined detection was calculated. Result The levels of serum AFP,AFP-L3,GPC3,and MMP2 in HCC patients were significantly higher than those of other non-HCC groups,and the differences were statistical significance(M =122.3 μg/L, 88.33 μg/L, 53.45 pg/ml, 701.3 μg/L;H =125.8, 167.5, 209.4, 210.4; P< 0.05). The diagnostic accuracy of the combined detection of four indicators was 89.3%, the sensitivity and specificity were 84.87% and 84.59%, respectively, and the area under the curve was 0.905, which was higher than that of single detection, there are significant difference in those three groups(P< 0.05). Conclusion The combined detection of serum AFP, AFP-L3, GPC3 and MMP2 are the risk factors of HCC ppatients, which is helpful to the early diagnosis and treatment of cancer in high-risk patients with hepatocellular carcinoma, and improve survival time of patients and the survival rate.