To investigate the clinical value of combined detection of serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) in the differential diagnosis of hepatitis C-related cirrhosis and hepatocellular carcinoma (HCC).Methods 48 patients with HCC (HCC group), 42 patients with hepatitis C-related cirrhosis (disease control group) and 30 healthy individuals (healthy group) who were admitted to the 900th Hospital of Joint Logistics Support Force from June 2020 to June 2021 were selected as the research subjects.General information and laboratory indexes of the 3 groups were collected.Serum AFP, CEA and CA199 levels in the 3 groups were detected, and the value of each index in differential diagnosis of hepatitis C-related cirrhosis and HCC was analyzed using the ROC curve.Results The levels of ALT and AST were significantly lower, and the level of TBIL was significantly higher in the HCC group than in the disease control group and the healthy group (P＜0.05).Serum AFP, CEA and CA199 levels decreased in order from the HCC group, the disease control group to the healthy group, with significant differences between any two groups (P＜0.05).The area under the curve and sensitivity of combined detection of serum AFP, CEA and CA199 for differential diagnosis of HCC (0.979 and 98.5%) were significantly larger than those of combined detection of liver function indicators (0.695 and 79.8%).Conclusion Combined detection of serum AFP, CEA and CA199 can significantly improve the differential diagnosis of hepatitis C-related cirrhosis and HCC