p21WAF1/CIP1 is a universal cyclin–dependent kinase (cdk) inhibitor, the expression of which is regulated by p53–dependent and p53–independent pathways. We examined p21WAF1/CIP1 expression in and p53 status of 21 primary hepatocellular carcinomas (HCCs) by reverse–transcriptase polymerase chain reaction (RT–PCR) and by PCR single–strand conformation polymorphism (PCR–SSCP) analysis. p21WAF1/CIP1 messenger RNA expression was reduced markedly in 8 of 21 HCCs (38.1%) and 5 of these 8 HCCs bore p53 mutations. The relative p21WAF1/CIP1 messenger RNA expression value of HCCs with p53 mutations (.73 ± .13 U, n = 6) was significantly lower than that of HCCs with wild–type p53 (1.00 ± 0.21 U, n = 14; P < .01). The p21WAF1/CIP1 expression levels in cancerous tissues (.73 ± .13 U) were significantly reduced in comparison with those in noncancerous tissues (.97 ± .13 U) (P < .01) in the 6 cases with p53 mutations. These data indicate that p21WAF1/CIP1 expression in HCCs is predominantly regulated by dependence on p53 and that reduced p21WAF1/CIP1 expression may participate in hepatocarcinogenesis.