Because epidermal growth factor (EGF) up-regulation is characteristic of the cirrhotic liver, we hypothesised that the EGF rs4444903 A > G functional polymorphism might be associated with a worse disease course in patients with chronic HBV infection. To verify this hypothesis, 170 HBV-positive patients (125 males) with a median age of 52 years were studied. Sixty-two of these patients were followed longitudinally for a median time of 21 years. Genotyping for the EGF rs4444903 A > G polymorphism was performed by the polymerase chain reaction-based restriction fragment length polymorphism assay. In the cross-sectional study, the EGF rs4444903 A > G polymorphism genotypic frequencies significantly differed between transplant patients (A/A = 20·4%, A/G = 52·3%, G/G = 27·3%) and HBsAg+ carriers (active and inactive: A/A = 35·7%, A/G = 47·6%, G/G = 16·7%, P = 0·036 for the linear trend). In the longitudinal study, the EGF rs4444903 A > G polymorphism was found to be an independent predictor of cirrhosis development (O.R. 7·73, 95% C.I. 1·21–49·5, P = 0·007). Three groups of patients were identified: A/A female homozygotes (n = 9), A/A male homozygotes (n = 13) and carriers of the G allele of either gender (n = 40). Cirrhosis did not occur among A/A females (n = 0/9), seldom occurred among A/A males (n = 2/13) and reached the highest frequency among G/* patients (n = 13/40, P = 0·026). In conclusion, the EGF rs4444903 A > G polymorphism appears to be associated with an unfavourable disease course of chronic HBV infection and cirrhosis development. This effect might be modulated, at least in part, by the gender of the patient.