Hepatocellular carcinoma (HCC) is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular prognostic markers is required. Many recent studies have shown that functional alterations of cell-cycle regulators can be observed in HCC. Among the various types of cell-cycle regulators, pl6 and p27 are frequently inactivated in HCC and are considered to be potent tumor suppressors. pl6, a Gl-specific cell-cycle inhibitor that prevents the association of cyclindependent kinase (CDK) 4 and CDK6 with cyclin Dl, is frequently inactivated in HCC via CpG methylation of its promoter region. pl6 may be involved in the early steps of hepatocarcinogenesis, since pl6 gene methylation has been detected in subsets of pre-neoplastic liver cirrhosis patients. p27, a negative regulator of the Gl-S phase transition through inhibition of the kinase activities of Cdk2/cyclin A and Cdk2/cyclin E complexes, is now considered to be an adverse prognostic factor in HCC. In some cases of HCC with increased cell proliferation, p27 is overexpressed but inactivated by sequestration into cyclin Dl-CDK4-containing complexes. Since loss of pl6 is closely related to functional inactivation of p27 in HCC, investigating both pl6 and p27 may be useful for precise prognostic predictions in individuals with HCC.