The abundance of p27^Kip1, an inhibitor of cell proliferation, is determined by Skp2-dependent proteolysis, the deregulation of which is associated with cancer progression. Lack of Skp2 results in p27^Kip1 accumulation as well as enlargement and polyploidy of hepatocytes. The role of Skp2 in cell growth and proliferation was investigated in Skp2-deficient mice subjected to partial hepatectomy. Skp2^−/− mice exhibited restoration of liver mass without cell proliferation; rather, hepatocytes increased in size, an effect that was accompanied by increased polyploidy and p27^Kip1 accumulation. Lack of Skp2 thus impairs hepatocyte proliferation, which is compensated for by cellular enlargement, during liver regeneration.