Liver polyploidisation, characterised by accumulation of tetraploid and octaploid cells, is found with increasing age and after administration of various drugs. The significance and mechanisms controlling polyploidisation are not understood but p53 is a candidate gene to be involved. We have investigated the effect of p53 on sodium phenobarbitone (PB)-induced liver proliferation and polyploidisation. Using p53 wild type (+/+), heterozygous (+/-) and homozygous (-/-) C57BL/6J mice, we measured ploidy and proliferation (BrdU incorporation) after 21 days oral administration of PB. Administration of PB caused a striking ploidy change compared with untreated controls, with an increase in 8n cells, and no difference noted comparing the p53 genotypes. BrdU positivity also increased significantly compared with controls, with the increase in BrdU positivity occurring in 8n cells. Our results confirm that PB is a hepatic mitogen that causes liver polyploidisation with a striking increase in 8n cells within the liver. p53 status does not appear to have any effect on this PB-induced ploidy change.