Background: Hepatitis C virus is one of the main causes of chronic liver disease worldwide. Egypt has the highest prevalence of HCV in the world, estimated nationally at 14.7% and is therefore confronted with a disease burden of historical proportions that distinguishes this nation from others. In HCC, 24P3 is overexpressed in tissues and closely associated with the proliferation and invasion of HCC cells.24P3 is mainly expressed in myeloid cells and later assigned to a cluster of at least three lipocalins on the long arm of human chromosome 9. Aim of the Work: was to shed the light on the role of oncoprotein 24p3 as a diagnostic marker in patients with hepatocellular carcinoma complicating hepatitis C virus. Subjects and Methods: This case control clinical study was carried out on 60 subjects who were divided into three groups: Group I: Twenty Patients diagnosed with HCC on top of HCV. Group II: Twenty Patients diagnosed with HCV without HCC. Group III: Twenty normal subjects with matched age and sex as a control group. Studied groups were subjected to abdominal ultrasonography, triphasic CT for patients with focal lesions, laboratory investigations including; liver function tests included hepatitis markers and serum 24P3, detected by enzyme linked immunosorbent assay (ELISA). Results: The study revealed a significant increase in AFP in Group I compared to Group II and in Group II compared to Group III. A significant difference P=0.001 was found among the three different groups. The cutoff for AFP was >20ng/mL, sensitivity was 70%, specificity was 85%, PPV 90%, NPV 65% and accuracy 78%. There was a significant increase of 24P3 in Group I compared to Group II and in Group II compared to Group III. A statistical significance p=0.001 was found among the three different groups. The cutoff for 24P3 was >250ng/mL and its sensitivity, specificity, PPV, NPV, and accuracy were all 100%. Based on the present study, 24P3 has a higher sensitivity, specificity and accuracy as compared to AFP, a famously used biomarker in HCC. Conclusion: Serum 24P3 levels in patients with HCV may be used as a guide for progression and prognosis of HCC. In these patients, if 24P3 levels were found to be high, serum alpha‑ feto protein and ultrasonographic examination could be repeated at more frequent intervals. This may also be used as a guide in terms of the treatment plan. Measurement of 24P3 in sera of large number of patients and follow up may pave the way to pick up early stage of HCC and showed its prognostic effect.