Cyclins, cyclin-dependent kinases (CDK), and CDK inhibitors (CKI) are frequently altered in neoplasm. p57(KIP2) is a member of the KIP (kinase inhibitory protein) family of CKI and is a potential tumor suppressor gene. p27(KIP1) is the most extensively studied KIP family member with respect to the clinical significance in human neoplasms. However, the clinical significance of p57(KIP2) expression in patients with human cancers, including hepatocellular carcinoma (HCC), remains unknown. This study examined whether p57(KIP2) expression has any impact on clinical behavior of HCC including prognosis. We examined an expression of p57(KIP2) by immunohistochemistry in 101 cases of various liver diseases, including 59 HCC. The p57(KIP2) expression in HCC was analyzed in association with the pathohistologic stage, differentiation, proliferating cell nuclear antigen (PCNA) expression status and several histopathologic factors of possible prognostic value, and patient survival. Immunohistochemical analysis revealed the frequent loss of p57(KIP2) in HCC, especially in moderately and poorly differentiated HCC. By Kaplan-Meier analysis, overall survival was significantly correlated with p57(KIP2) expression and PCNA, and multivariate analysis showed p57(KIP2) was an independent prognostic factor. When the status of p57(KIP2) and PCNA were combined, cases positive for p57(KIP2) and with a low expression of PCNA had a significantly better prognosis than those negative for p57KIP2 and/or with a high expression of PCNA. These data indicate that loss of p57(KIP2) is a frequent event in HCC, especially in poorly differentiated HCC, suggesting that p57(KIP2) might play a role in the differentiation of HCC. In addition, p57(KIP2) expression status is an independent prognostic factor for patients with HCC, and the loss of p57(KIP2) is correlated with poor prognosis. New therapeutic options might be provided by the combination of the loss of p57(KIP2) and expression of PCNA.