Background: Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy. Early detection of HCC is extremely important in improving the survival of patients. Alpha-fetoprotein (AFP) was commonly used as a predictor for HCC, but it was associated with low sensitivity and specificity. Thioredoxin (TRX) is a ubiquitous protein that was suggested to be elevated in cases with HCC. Objective: To evaluate the value of serum thioredoxin as a diagnostic marker of HCC versus alpha-fetoprotein in cirrhotic HCV patients. Materials and methods: This study included 96 patients divided into; groups I included, patients with liver cirrhosis, and group II included, patients with HCC on top of a cirrhotic liver. Both groups were successfully undergoing treatment of HCV with direct-acting antiviral (DAAs). Basic data, clinical examination, and laboratory analysis were obtained from all the cases. Human thioredoxin detection was done using Human TRX kits. Results: There is statistically significant increased TRX, AFP, APRI, and FIB4 among hepatocellular carcinoma group versus cirrhotic group. The ROC curve analysis demonstrated that TRX at a cut-off value of 198.19 (IU/ml) has 85.4% sensitivity and 89.6% specificity for differentiating HCC cases from cirrhotic cases with 89.1% PPV, 86% NPV, and AUC equal to 0.841. Both, AFP at a cut-off of 24 (ng/ml)and combined AFP and TRX had 93.8% sensitivity and 97.9% specificity with AUC equal to 0.99 for differentiating HCC cases from cirrhotic cases. Conclusion: Thioredoxin is a novel biomarker that revealed good sensitivity in the prediction of HCC on top of liver cirrhosis especially if combined with AFP.