Background and aim: To evaluate the role of chemokine CC ligand 20 (CCL20) as a biomarker for hepatocellular carcinoma (HCC). Patients and methods: Ninety patients in four groups were enrolled in this prospective cross-sectional study: 30 with HCC (group I), 30 with liver cirrhosis (group II), 15 with hepatitis C virus infection (group III), and 15 healthy blood donors as controls. Alpha fetoprotein (AFP), CCL20 and vascular endothelial growth factor (VEGF) were measured in all groups. Results: Serum levels of CCL20 were significantly different among the study groups (F=230.979, p<0.001). The highest level was found in HCC patients (57.305 +/- 6.386 pg/mL) followed by patients with cirrhosis (45.999 +/- 5.165 pg/mL) compared with 22.781 +/- 5.986 pg/mL and 18.585 +/- 3.554 pg/mL in asymptomatic patients with HCV infection and controls, respectively. In HCC patients, CCL20 significantly correlated with VEGF (r=0.559, p=0.001), AFP (r=0.814, p<0.001), Child score (r=0.748, p<0.001), and tumor size (r=0.825, p<0.001). The cutoff value of CCL20 for the detection of HCC in HCV-infected patients was 54 pg/mL with 93.1% accuracy, 89.6% negative predictive value, 92.6% positive predictive value, 83.3% sensitivity, and 93.3% specificity. In patients with cirrhosis, CCL20 significantly correlated with VEGF (r=0.455, p=0.011), AFP (r=0.975, p<0.001), and Child score (r=0.977, p<0.001). Conclusion: CCL20 may be used for the detection of HCC in HCV-infected patients with comparable specificity and higher sensitivity than AFP.