Background and Aims: Diagnostic modalities for hepatocellular carcinoma (HCC) as markers, sonography, and CT have contributed to the early detection of HCC but are still not sensitive enough. Human telomerase RNA subunit (hTERTmRNA) has been identified in many cancers and claimed to be reactivated in HCC. To investigate hTERT-mRNA in the peripheral blood of HCC and chronic liver disease (CLD) patients and correlate its level with alpha feto protein (AFP), the serological marker for HCC.Methods: The study was conducted on 44 patients selected from the National Liver Institute. Patients included Group I (22 patients diagnosed to have HCC), Group II (22 patients with CLD), and 12 apparently healthy volunteers as controls (Group III). All selected individuals were subjected to history taking, a clinical examination, abdominal sonography and laboratory investigations as liver function tests (LFTs), cell blood count (CBC), hepatitis viral markers, AFP, and realtime polymerase chain reaction (PCR) Quantitative detection of -mRNA expression, encoding for telomerase catalytic subunit.Results: There was a significant elevation of AFP levels in the HCC group compared to both the CLD and control groups (P < 0.00, P < 0.001). The mean hTERT-mRNA expression in HCC patients was significantly higher than both CLD patients and controls (P < 0.001, P < 0.001). hTERT-mRNA was correlated with AFP and tumor size (P < 0.05, P < 0.001). The AFP cutoff level (185 ng/ml) resulted in a 63.6% sensitivity, a 85.3% specificity; a 89.3% positive predictive value (PPV) level, a 76.2 % negative predictive value (NPV) level and a 83.4% accuracy for HCC prediction. The hTERT-mRNA cutoff level (112.5 copies/ml) showed a 77.3% sensitivity, a 97.1% specificity, a 98% PPV level, a 79.2 % NPV level, and an accuracy of 84% for HCC prediction. Combining hTERT-mRNA and AFP increased diagnostic accuracy to 90.5%. Both markers had a 84.1% sensitivity, a 86.4% specificity, a 86.4% PPV level, and a 88.3 % NPV level.Conclusions: hTERT-mRNA is thought to be superior to AFP in CLD patients and could be a marker for the early diagnosis of HCC. Combined hTERT-mRNA and AFP would augment early detection and successful follow-up of HCC patients.