Previously, we have shown that over-expression of either E2F1 or c-Myc promotes hepatocarcinogenesis and that E2F1 mice acquire HCC more rapidly than c-Myc transgenic mice. We also found that co-expression of E2F1/c-Myc further accelerates liver cancer development. Here we describe that the deregulated expression of these two transcription factors also affects hepatic ploidy during post-natal liver growth and before the onset of tumors. Oncogenic activity of E2F1 and/or c-Myc was associated with a persistent increase in hepatocyte proliferation. However, E2F1-mediated cell proliferation favored the predominance of diploid cells characteristic of pre-neoplastic type of liver growth whereas c-Myc functioned to accelerate age-related hepatocyte polyploidization. Similarly, proliferative advantage conferred by co-expression of E2F1 and c-Myc increased the frequency of diploid cells at a young age. Thus, the opposing effects of E2F1 and c-Myc on hepatocyte ploidy suggest that these two transcription factors have different mechanisms by which they control liver proliferation/maturation and ultimately, carcinogenesis. (C) 2003 Elsevier Science (USA). All rights reserved.