Background: Hepatocellular Carcinoma (HCC) is the commonest primary cancer of the liver. Incidence of HCC is increasing to be the fifth most common cancer and the second most frequent cause of cancer-related death globally. Kupffer cells and hepatocytes can express elevated levels of CD40 in hepatitis C virusassociated chronic liver disease. The CD40 CD40ligand co stimulatory pathway is associated with liver injury and hepatocyte apoptosis. Objective: This study aimed to evaluate efficacy of soluble CD40 ligand as an early marker in diagnosis of HCV- related HCC. Subjects and methods: This is a case control study. It was conducted in Internal Medicine and Microbiology Departments, Faculty of Medicine, Zagazig University Hospitals along six months. Ninety subjects were included in this study. They were classified into three groups as follows: Group 1 that included 30 (18 males and 12 females) apparently healthy subjects aged between 44 to 67 years old. Group 2 that included 30 patients (20 males and 10 females) aged between 41 to 65 years old with chronic HCV infection without HCC. Group 3 that composed of 30 patients (22 males and 8 females) aged between 44 to 65 years old with chronic HCV infection with HCC. Results: There was statistical significance increase in CD40 level in group 3 compared to the other two groups (1 and 2). There was significant negative correlation between serum CD40L with both Hb and PLT, while there was significant positive correlation between CD40 level with T.bilirubin, D.bilirubin, ALP, INR and AFP. Conclusion: Serum CD40L is significantly increased in patients with chronic HCV-related HCC. So, CD40L can be used as a non-invasive pro inflammatory marker for diagnosis of HCC.