To clarify the clinical significance of the mutation of p53 gene in hepatocellular carcinoma (HCC), 90 resected specimens from Japanese patients were assayed using a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. p53 mutations were detected in 25 cases (27.8%) at exons 4, 5, 6, 7, and 8, and the most frequent region of the mutation was at exons 5 and 7. No statistically significant correlation was observed between the p53 mutations and the clinical features except for the preoperative alpha-fetoprotein (AFP) level (P < .05). According to the pathological features, prognostic factors, such as size of the tumor, vascular invasion, fibrous capsule infiltration, and intrahepatic metastasis, showed no relationship to the existence of the mutation. However, p53 mutations were significantly associated with the degree of differentiation of HCC; that is, the mutation was found in 19 cases of 53 poorly differentiated HCCs (35.9%) and 2 of 3 cases of anaplastic HCCs (66.7%). The presence of p53 mutations was associated with a shortened cancer-free survival (P < .001, by log rank test) and a shortened survival (P < .05). A multivariate analysis by the Cox regression analysis showed that the p53 mutations were an unfavorable prognostic factor related to recurrence (P < .005), which is especially significant within the first postoperative year. These results suggest that the mutations of p53 gene of HCC might be an independent prognostic predictor to help in the selection of candidates who should undergo more intensive postoperative treatment.