It is difficult to diagnose multicentric occurrence in advanced multinodular heptocellular carcinoma (HCC) based only on morphological criteria. In the present study the authors analyzed clonality using differences in the mutation pattern of the p53 gene in addition to morphological results and assessed the clinical background and usefulness of surgical treatment for multicentric HCCs including advanced cases. Among 74 multinodular HCC cases, 10 (14%) were diagnosed as multicentric HCC lesions and 48 (65%) as intrahepatic metastatic tumors according to morphological criteria. In the remaining 16 cases, the mutation pattern of the p53 gene was examined and 6 (38%) patients were found to have a mutation. Four of these 6 patients were diagnosed as multicentric HCCs and the other 2 as intrahepatic metastatic HCCs according to the p53 mutation pattern. The incidence of p53 mutation increased with tumor dedifferentiation (p<0.05) in informative cases. In the analysis of prognosis in relation to clonality, both the cumulative survival and the cancer-free survival rates were significantly higher in the multicentric HCC including advanced cases than in metastatic HCCs. In conclusion, this is considered to be a useful method for diagnosing clonality in advanced multinodular HCC cases post- and pre-operatively and for choosing adequate treatment. Surgical resection is a useful treatment for advanced multicentric HCC cases.