To investigate the possible roles of p27(KIP1) and p21(WAF1/CIP1), inhibitors of cyclin-dependent kinases, in hepatocellular carcinoma (HCC), we examined p27(KIP1) and p21(WAF1/CIP1) expression in primary HCC with immunohistochemistry and Northern blot hybridization and correlated the results with clinicopathologic features and survival. With immunohistochemistry, positive staining for p27(KIP1) and p21(WAF1/CIP1) protein was found in 54.3% and 63.8% of HCCs, respectively. Both p27(KIP1) and p21(WAF1/CIP1) scores of the tumors were significantly higher than those of the corresponding nontumorous livers (P <.0001 and.009, respectively). Higher levels of p27(KIP1) were associated with a lower incidence of direct liver invasion (P =.021) and, less significantly, with a low incidence of multiple tumor nodules (P =.056). Patients whose tumors had higher p27(KIP1) protein scores had longer disease-free survival (P =.011). For p21(WAF1/CIP1), in contrast to the overexpression of the p21(WAF1/CIP1) protein in HCC, the relative amounts of p21(WAF1/CIP1) messenger RNA (mRNA) in the tumors were found to be reduced compared with those of the nontumorous livers (P =.039). In conclusion, p27(KIP1) and p21(WAF1/CIP1) proteins were frequently overexpressed in HCC. Longer disease-free survival rates were seen in patients whose tumors had higher p27(KIP1) expression. The accumulation of p21(WAF1/CIP) protein in the presence of a reduced mRNA level suggests probable posttranslational protein stabilization, and the reduced transcription of p21(WAF1/CIP) may represent a form of dysfunction of cyclin-dependent kinase inhibitor involved in hepatocarcinogenesis.