The study's objective was to evaluate the clinical significance of sCD40L in HCV-associated hepatocellular carcinoma (HCV-HCC) patients. Sera concentration of circulating sCD40L and IL-10 were assayed using ELISA in 30 HCVpositive patients with HCC, 30 HCV-positive patients with liver cirrhosis and 30 age-matched healthy volunteers with negative anti-HCV-Ab as a control group. Serum sCD40Lshowed statistically-significant high levels in HCV-HCC patients compared to HCV-cirrhotic patients and normal controls (P < 0.001). Serum sCD40L had higher diagnostic value in HCC patients compared with serum AFP. High sensitivity and specificity of sCD40L was observed compared to AFP (90%, 86.7% and 83% and 80% respectively). Significant positive correlation was detected between serum sCD40L and IL-10(r = 0.85 P < 0.001), AFP (r = 0.62 P < 0.05) and tumour staging (r = 0.5 P < 0.05). The study concluded that sCD40L is a valuable diagnostic tool in early diagnosis and screening for HCV and HCC as well as routine follow up of HCV cirrhosis patients. Assessment of serum IL-10 levels in HCV patients may provide a possible predictive marker for disease progression.