Hepatoblastoma comprises only 1% of all cancers in childhood. Because of its low frequency, a small number of prognostic factors are described in hepatoblastoma and most of them are related to resectability. Microarray studies showed a large number of underexpressed genes in hepatoblastoma. Because aberrant DNA methylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation, this could be involved with gene downregulation in these tumors. Despite the rarity of hepatoblastoma, this study evaluated the methylation pattern of 25 genes in 20 paraffin-embedded tumor specimens and five non-neoplastic liver samples (normal control) by quantitative methylation-specific PCR (QMSP). The examination of the methylation profile of hepatoblastoma samples and normal liver specimens revealed a high tumor-specific DNA hypermethylation in the promoter regions of five genes (APC, CDH1, MT1G, RASSF1A, and SOCS1). Furthermore, MT1G hypermethylation showed a significant correlation with poor prognosis of patients with hepatoblastoma. This study represents the first quantitative evaluation of promoter hypermethylation in hepatoblastoma and demonstrated that aberrant methylation is a frequent event in this malignancy. Furthermore, our data provide evidence that MT1G hypermethylation may be useful as prognostic indicator for this disease and suggest that patients with hepatoblastoma may benefit from demethylating drug treatments.