Hepatocellular carcinoma (HCC) is one of the most common tumours world wide. The prognosis of HCC is poor the only curative option is liver resection or transplantation. Genetic abnormalities seen in HCC tumours mainly include inactivation of tumour suppressor genes and inactivation of oncogenes. The tumour suppressor gene of most interest is p53. Gene therapy is an exciting approach because it offers the potential of correcting the underlying genetic defect. Forty patients suffering from HCC (group I) were included in this study, and 10 patients suffering from chronic active HCV (group II) served as a control group for studying the p53 gene expression. In group I patients out of 40 patients 26 showed p53 gene over expression, none of the group II patients showed gene over expression. Ten patients suffering from post-hepatitic cirrhosis with hepatic focal lesions, proven to be hepatocellular carcinoma were included for an open label, randomised prospective study, to receive either ethanol injection (PEI) or Ad E1B deleted. They underwent: Complete medical history, Laboratory screening, abdominal ultrasonography, computed tomography (CT) scans of the abdomen and pelvis. p53 gene expression was studied in tumour tissue (immunohistochemical). Serum samples were taken to detect the presence of adenovirus and antibody titre. PEI was given using the Livraghi 1995 technique. Toxicity and complications in ethanol groups were pain and fever. In Gene therapy group complications were minimal, in the form of fever. Patients response in Gene therapy group was one patient had partial response 4 had progressive disease. In PEI group one patient had partial response 4 had progressive disease. Conclusions: There is a high incidence of p53 gene over expression in HCC tumours. Injection of adenovirus is well tolerated, and further trial to determine its efficacy is indicated.