Background: Early detection of hepatocellular carcinoma is mandatory for treatment. Alpha Fetoprotein (AFP) has limited sensitivity in detection of small sized (early) lesions. Thus, new serological markers with better sensitivity and specificity are needed. Aim of the study: To evaluate the diagnostic value of intercellular adhesion molecules (ICAM), beta catenin (β-catenin), interleukin 8 (IL-8) and soluble tumor necrosis factor receptor II (sTNFr-II) in the early detection of Hepatocellular carcinoma (HCC).Subjects and methods: The study was conducted on 3 groups of patients in addition to 100 apparently healthy age and sex matched control subjects. Group (1) included 100 patients with HCC (on top of HCV). Group (2) included 100 patients with HCV related liver cirrhosis. Group (3) included 100 patients with HCV related chronic hepatitis. Serum levels of IL-8, ICAM, sTNFrII and β-catenin were tested in all patients and control subjects. The sensitivity and specificity of the studied markers were calculated and compared.Results: Smoking and diabetes mellitus were more prevalent in the HCC group (p<0.001). Serum level of AFP was significantly elevated in the HCC group compared to other studied groups (p<0.001). IL-8 was found to decrease in patients with HCC compared to patients with liver cirrhosis. ICAM, β-catenin and sTNFr-II showed increased serum levels with HCC. As for the sensitivity and specificity of the AFP and the four studied serological markers for diagnosing HCC; AFP had 62% sensitivity and 88% specificity at a cut off level 80.5ng/ml. IL-8 had a cut off level of 51.5pg/ml with a sensitivity of 70.4% and a specificity of 52.3%. ICAM had sensitivity and specificity of 75.8% and 71.8% respectively at a cut off level 778ng/ml. sTNFr-II at the cut off level 6239.5pg/ml showed a sensitivity of 86.3% and specificity of 51.8%. However, both markers didn’t show a significant difference between HCC patients and other patients. Lastly, β-catenin had a sensitivity of 70% and specificity of 68.6% at a cut off level 8.75ng/ml with a significant difference between HCC patients and other patients. Combining ICAM to AFP, the sensitivity reached up to 85.73% and the specificity improved to 79.9%. Combining AFP to β-catenin showed a sensitivity of 91.69% & and specificity of 78.3%. Combining β-catenin and ICAM, a sensitivity of 93.67% and a specificity of 86.1% could be reached.Conclusion: The use of β-catenin as an independent HCC marker should be considered. Combining the AFP to β-catenin or to ICAM improves the sensitivity, specificity and overall accuracy of HCC detection. Further studies are needed to assess their role in follow up and estimation of the prognosis of HCC.