Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide. Early diagnosis of HCC remains a challenge and diagnosis is usually achieved by biomarkers, but up to date, there is not a perfect single biomarker for this tumor. The diagnostic and predictive abilities of the biomarkers are limited by the heterogeneous nature of the HCC and to improve the predicatively and sensitivity, combinations of biomarkers, or a panel of biomarker combinations and clinical parameters as well as laboratory test results, might be required The objective of the present study was to assess a combination of biomarkers that is reliable in the diagnose and the prognosis of HCV-related HCC. For this purpose, a group of biomarkers including two novel ones; the vascular adhesion molecule-1 (VCAM-1) and soluble platelet endothelial cell adhesion molecule 1(sPECAM-1) were measured in Egyptian patients with chronic HCV and HCC. The ROC analyses were applied to evaluate the specificity and sensitivity of the biomarkers and come up with a recommendation for the employment of these markers to predict early development of hepatitis C to hepatocellular carcinoma. In the present study, 120 individuals from the National Hepatology and Tropical Medicine Research Institute, enrolled during the period from September 2014 to March 2017, were divided into four major groups; the control group which comprised 20 individuals.HCV group comprising 50 patients with chronic hepatitis C genotype 4, HCC group comprising 25 patients with HCC without HCV, and finally the HCC+HCV group comprising 25 patients with proven chronic hepatitis C genotype 4 and hepatocellular carcinoma. All the study patients were subjected to laboratory investigations which included liver functions, oxidative stress, LDH, AFP, IL-10, IL-6, IL-8, TNF-α, IFN-γ, Caspase-3, MCP-1, VCAM-1 and sPECAM-1, to predict early development of hepatitis C to hepatocellular carcinoma. The results suggested that there were significant differences in most of the liver functions, LDH, oxidative stress, IL-8, TNF-α, MCP-1 and AFP between healthy individuals and the groups with the disease forms. There were no significant correlations between serum IL-6, IL-10, INF-γ, VCAM-1, sPECAM-1 and caspase-3 with HCV or HCC. The ROC curve analyses revealed that sPECAM-1 and sVCAM-1 were not sensitive biomarkers for HCC. AFP levels were highly specific, but insufficiently sensitive to detect HCC. Serum PECAM and serum VCAM were not sensitive indicators for HCC diagnosis because of their low discriminative power between groups. Consequently, they were passive with respect to their predictive power in the progression of HCV-related HCC development. In conclusion, relying on a single marker for the diagnosis of HCC is not possible by employing the nowadays widely used markers in diagnostic practice.