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 unsatisfactoryand questionable because of low sensitivity, therefore there is a strong demand by clinicians for new HCC-specific biomarkers.AFP mRNA has lately been detected in tumor tissue of HCC but not in nontumorous tissue, and its gene expression is reported to be modulated by hypomethylation of the AFP gene. The presence of circulating HCC cells, which may be released from tumor foci into the circulation, could be an indicator of hematogenous spread of tumor cells leading to extra hepatic metastasis of HCC Aim: The aim of this study was thus to investigate the role of serum AFP mRNA a diagnostic non invasive marker for HCC and to assess its sensitivity and specificity as a marker of HCC in patients.Methods: The present study was performed on 38 patients and 20 healthy subjects; 18 patients had hepatocellular carcinoma and 20 had chronic liver diseases. HCC diagnosis based on liver tumor characteristics detected by imaging studies (ultrasonography and spiral CT), and/or histopathology. The clinicopathological data of the patients at initial diagnosis was collected, and included history taking, examination, CBC, liver function tests, serum AFP concentration and ultrasound examinationResults: We found that there was a significant elevation in the median serum AFP in HCC group when compared to control group . The median serum AFP-m RNA in ten HCC patients was 93.4(0.00-107.5) copies/µl and it wasn’t detected neither in CLD nor control groups. A cutoff level of AFP at 10ng/ml (best cutoff level for the study) it had a sensitivity of 55% and a specificity of 28%. The cutoff level of AFP mRNA for diagnosis of HCC in this study was 47 Copies/µl with a sensitivity and specificity of 55% and 100% respectively. A statistically significant positive correlation could be estimated between AFP m-RNA and serum AFP.Conclusion:The present data provide circumstantial support for the hypothesis that AFP m-RNA in blood reflects the presence of circulating HCC cells, and therefore can be used as a useful diagnostic marker of HCC. In patients where AFP determination is alone clueless in the diagnosis of HCC, the addition of AFP mRNA increases the sensitivity from 55% to 66%. AFP m-RNA has a specificity of 100% in diagnosis of HCC versus CLD.