ERCC1-XPF is the endonuclease that cuts 5′ of the damage in nucleotide excision repair (NER). Unlike other NER proteins, ERCC1-XPF is also involved in recombination and the repair of DNA interstrand cross-links. Unique among the NER gene knockouts, Ercc1 null mice are severely runted with high levels of hepatocyte polyploidy. To understand the link between DNA repair deficiency and polyploidy we have compared the premature polyploidy in Ercc1 null liver with the normal development of polyploidy in aging control mice. Polyploidy was accelerated dramatically in Ercc1 null hepatocytes, such that ploidy levels were equivalent in 3-week-old Ercc1 null and 1- to 2-year-old wild-type mouse liver. Levels of the cyclin-dependent kinase inhibitor, p21, were increased in the nuclei of Ercc1 null hepatocytes, and this increase was concentrated in, but not confined to, the polyploid hepatocytes. Much lower levels of p21 messenger RNA (mRNA) were found in old wild-type liver with equivalent levels of ploidy. We suggest that the more rapid accumulation of DNA damage in Ercc1 null liver leads to an increase in p21 levels, but that there is not a simple direct link between p21 levels and premature polyploidy. The failure to observe any link between p21 levels and polyploidy in aged wild-type liver may be attributable to the much lower levels of accumulated DNA damage, the much greater timescale involved, or the existence of a p21-independent mechanism for polyploidy. In conclusion, the premature polyploidy in Ercc1-deficient liver differs from the normal aging-related process. (Hepatology 2003;38:958–966).