This study examined the utility of stratifying children with medulloblastomas by a combination of refined histopathological classification and molecular cytogenetic evaluation. Detailed histopathological classification of tumors from a cohort of patients (n = 87) composed mainly of children entered into the International Society of Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group PNET3 trial (n = 65), included identification of the large cell/anaplastic phenotype. Fluorescence in situ hybridization was used to detect chromosome 17 abnormalities, losses of 9q22 and 10q24, and amplification of the MYCC and MYCN oncogenes. The large cell/anaplastic phenotype, which was present in 20% of medulloblastomas, emerged as an independent prognostic indicator. Loss of 17p13.3 (38% of medulloblastomas) was found across all of the histopathological variants, whereas MYCC/MYCN amplification (6%/8% of medulloblastomas) was significantly associated with the large cell/anaplastic phenotype. Both of these genetic abnormalities emerged as prognostic indicators. Loss of 9q22 was associated with the nodular/desmoplastic medulloblastoma variant, whereas loss of 10q24 was found in all of the variants. Together with metastatic tumor at presentation, the large cell/anaplastic phenotype, 17p13.3 loss, or high-frequency MYC amplification defined a high-risk group of children whose outcome was significantly (P = 0.0002) poorer than a low-risk group without these tumor characteristics. Combined evaluation of novel histopathological features and molecular cytogenetic abnormalities promises to allow stratification of patients with medulloblastoma, such that those likely to be cured will be spared the side effects of maximal therapy, which can be targeted at those with aggressive disease.