BACKGROUND: The epidermal growth factor (EGF) rs4444903 A>G polymorphism has been associated with the development of liver cancer, which commonly complicates cirrhosis of viral origin; however, whether this polymorphism might be associated with fibrosis progression in chronic viral hepatitis is unknown. The present study was performed to assess the allelic and genotypic frequencies of the rs4444903 A>G polymorphism in patients with chronic hepatitis C virus HCV infection and to ascertain whether this polymorphism might be an independent predictor of the degree of fibrosis. METHODS: An RFLP-PCR technique was used to genotype 645 patients (211 with cirrhosis); 528 were referred for the diagnosis and treatment of chronic hepatitis C, and 117 were transplanted for HCV-related end stage liver disease. A group of 428 healthy subjects served as a control. All the subjects were of Caucasian ethnicity. RESULTS: The EGF rs4444903 A>G polymorphism genotype frequencies in HCV chronic infected patients were as follows: A/A=227 (35.3%), A/G=328 (50.9%), and G/G=90 (14.8%). Genotype frequencies were found to differ between patients with an Ishak staging score⩽2 (A/A=117, A/G=157, G/G=34) and patients with a score>2 (A/A=110, A/G=171, G/G=56, p=0.038). A highly significant linear relationship between increasing stage scores and EGF genotype was detected in younger patients (A/A: 2.02±0.18, A/G: 2.55±0.17, G/G: 3.00±0.32, p=0.008). However, no significant association was detected between the stage score and EGF genotype in older patients (A/A: 3.79±0.19, A/G: 3.64±0.15, G/G: 3.98±0.30 p=0.579). CONCLUSIONS: The EGF rs4444903 A>G polymorphism may facilitate liver fibrosis progression in Caucasian patients with chronic hepatitis C, especially in younger patients.