ABSTRACT: The current diagnosis of HCV infection includes serological assays and nucleic acid amplification technology (NAT) for assessing serum anti-HCV antibody and HCV viremia, respectively. The objective of this study was to evaluate the diagnostic potential of HCV-NS4 in comparison with polymerase chain reaction. HCV-NS4 antigen was detected in 300 Egyptian serum samples of patients with different liver pathology. In addition to serum samples from 50 asymptomatic individuals and serum samples from 50 healthy individuals as a normal control. Areas under the ROC curves (AUC) were used to assess and com pare diagnostic accuracy of ELISA for HCV-N S4 with quantitative HCV-RNA as a gold standard. The positive rate of HCV-NS4 antigen was 32% (16/50) in 50 asymptomatic individuals, 78% (156/200) in 200 patients with liver fibrosis, 80% (40/50) in 50 patients with liver cirrhosis and 82% (41/50) in 50 patients with HCC. Using healthy individuals, the specificity of the HCV-N S4 antigen was 100 %. The area under ROC curve of HCV-NS4 antigen for discriminating patients with different liver pathology from those healthy individuals was 0.89 and (P < 0.0001). In conclusion, the HCV-NS4 antigen detection method could be done in routine laboratories without the need for special equipment or training.