Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies. Its high mortality rate is mainly a result of intra-hepatic metastases. To investigate the detailed genetic mechanisms in cancer metastasis, we compared the expression profiles of 20 HCCs with intrahepatic metastasis and 10 HCCs without intrahepatic metastasis using an oligonucleotide array. Of the approximately 12600 genes that were analyzed, we identified 34 genes whose expression levels were significantly correlated with intrahepatic metastasis (PH 0.05). Of these genes, we further investigated the expression of high-mobility group I (Y)[HMG-I (Y)] protein. Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) confirmed that HMG-I (Y) was upregulated in HCC with intrahepatic metastasis, compared to its level in HCC without intrahepatic metastasis. Further immunohistochemical examination of HMG-I (Y) revealed a significant overexpression in HCC with intrahepatic metastasis, compared with that in HCC without intrahepatic metastasis (PH 0.05). These results indicate that the molecular signatures of HCC with intrahepatic metastasis and of HCC without intrahepatic metastasis are clearly different. HMG-I (Y) expression was associated with intrahepatic metastasis and may be a predictive marker of HCC intrahepatic metastasis.(Keio J Med 53 (2): 90–97, June 2004)