Background: Thioredoxin (TXN) is an important regulator of redox balance in the cell and has been implicated as playing a role in cell survival in many conditions including cancer. Aim: To evaluate the role of TXN serum level and TXNDC5 gene polymorphisms in diagnosis of hepatocellular carcinoma (HCC) in cirrhotic Egyptian patients due to hepatitis C virus (HCV). Subjects and Methods: Thirty five cirrhotic patients with HCC patients, thirty five cirrhotic patients without HCC patients and 20 healthy volunteers were enrolled in this study. TXN serum level was quantitated using by human thioredoxin enzyme-linked immunoassay (ELISA) and molecular study of TXNDC5 (rs1225943) polymorphism using real-time polymerase chain reaction by Taqman allele discrimination was done for all subjects. Results: Showed that TXNDC5 (rs 1225943) AA genotype was the most frequent genotype in HCC patients and the most frequent allele was A allele in HCC patients, without significant difference of TXNDC5 (rs 1225943) polymorphism in the studied groups and TXN serum level was significantly higher in HCC patients (mean 40.2±11.92) than in cirrhotic patients (mean 9.5±5.66) (p < 0.001) and normal controls (mean 7.1±1.67) (p < 0.001), and AFP ≥ 41 (ng/ml) and TXN serum level ≥14.3 (ng/ml) are diagnostic for HCC presence. Conclusion: Serum Thioredoxin level may be used as a molecular marker for HCC diagnosis, and TXNDC5 (rs 1225943) polymorphism was not associated with the risk of HCC in HCV-cirrhotic patients.