Mutations of the p53 detected in human hepatocellular carcinomas suggest that its inactivation is a critical step in hepatocellular carcinogenesis. In order to test whether the expression of p53 is compatible with the transformed phenotype of hepatoma cells, we transfected Hep 3B cell line with p53 expression vectors. This cell line, which contains integrated hepatitis B virus sequences, is a good model to study whether the wild-type p53 can function as a tumour suppressor gene in virus-related hepatocellular carcinoma. Wild-type and mutant p53 (Ala143)-expression vectors containing a neoR gene were used. The number of antibiotic-resistant colonies was six times lower after transfection with wild-type p53 vector as compared to the mutant vector. As measured by a specific radioimmunoassay, six of eight (75%) colonies randomly selected after mutant p53 transfections expressed the transfected mutant p53 protein. In contrast, out of eight colonies from wild-type p53-transfections, none expressed detectable p53 protein. The absence of p53 protein was due to the selective deletion of transfected wild-type p53 cDNA sequences. These studies demonstrate that the growth of hepatocellular carcinoma cells is not compatible with the expression of wild-type p53. Therefore, p53 should be considered as a tumour suppressor gene in hepatocytes.