Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and it is one of the major causes of death. HCC is now a rather common malignancy in Egypt which usually develops on top of liver cirrhosis secondary to viral infection. HCC diagnosis is a multistage process including clinical, laboratory, imaging and pathological examinations. The AFP diagnostic accuracy is unsatisfactory and questionable because of low sensitivity, therefore there is a strong demand by clinicians for new HCC-specific biomarkers. The lens culinaris agglutinin (LCA)-reactive alpha-fetoprotein (AFPL3) is percentage of total AFP concentration and it is the major glycoform in the serum of HCC patientsAim: The aim of this study was to investigate the potential role of Hepatoma-Specific AFP (AFPL3) as a diagnostic non-invasive marker for HCC, in order to add a beneficial diagnostic value in patients with low levels of alpha-fetoprotein (AFP) and suspected to have HCC.Methods: This study was conducted on 27 HCC patients with and 30 cirrhotic patients with no evidence of HCC; as well as 31 healthy subjects who served as control group.We determined the level of AFP and AFPL3 for all cases together with full clinical assessment, liver biochemical profile, conventional ultrasound (US), abdominal triphasic CT scan.Results: We found that there was positive correlation between AFPL3 and total AFP, also AFPL3 was significantly elevated in the HCC group comparing to cirrhosis and control groups. The higher total AFP the higher AFPL3 percentage. The diagnostic sensitivity of AFP at a cutoff 22.6 ng/ml was 83% and the specificity was 83%. The cutoff level of AFPL3 for diagnosis of HCC in this study was 5%, with a sensitivity and specificity of 96% and 83% respectively. There was a significant elevation of AFPL3 with patient whose total AFP level (10-200) with increasing specificity and PPV to100% at cut off 3.8%. There was no positive correlation between AFPL3 and the number or the size of hepatic focal lesions in HCC patients. Conclusion: AFP-L3 is a useful adjunct marker in the diagnosis of HCC, in the grey zone patients where AFP determination is alone clueless in the diagnosis of HCC, the addition of AFP-L3 has a 100 % specificity and 100% PPV. Outside the grey zone patients AFP may suffice in the diagnosis of HCC, where AFP-L3 is not detectable if total AFP is less than10 ng/dl and if total AFP is more than 200 it would obviously trigger calling for another confirmatory modality. AFP-L3 offers no correlation to the clinical or ultrasonographic features of tumors