Background Overexpression of epidermal growth factor (EGF) in the liver induces transformation into hepatocellular carcinoma (HCC) in animal models. Polymorphisms in the EGF gene modulate EGF levels. Objectives To evaluate the effect of EGF gene single nucleotide polymorphism and to assess its correlation with the risk of HCC in patients with chronic liver diseases. Patients and methods The present study included 80 participants divided into four groups: group 1 included 20 asymptomatic healthy control volunteers, group 2 included 20 patients with chronic hepatitis C viral (HCV) infection, group 3 included 20 patients with liver cirrhosis, and group 4 included 20 patients with HCC. For all participants, the following investigations were performed: routine laboratory investigations including complete blood count, liver function tests, sero markers of hepatitis viruses HBsAg, HCV-RNA by quantitative polymerase chain reaction, and a-fetoprotein. DNA was extracted from whole blood for detection of single nucleotide polymorphism of the EGF by polymerase chain reaction, followed by restriction fragment length polymorphism. Results We found a significant difference between both patients with HCC and HCV versus controls in terms of the G carrier (GG and GA; 80 vs. 40%, P<0.05). In addition, the cirrhotic and chronic hepatitis C patients with GG had three-fold and 2.3-fold odds ratio for developing HCC, respectively. Conclusion The EGF 61GG genotype might be associated with a high risk for the development of HCC in Egyptian patients with chronic liver disease. Eur J Gastroenterol Hepatol 24:458-463 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.