Purpose No reliable classification exists for the therapeutic stratification of children with ependymoma, such that disease-risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study examined associations between clinicopathological and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for grading this heterogeneous tumor. Methods Intracranial ependymomas (n=146) from children treated on the RT1 trial at St. Jude Children’s Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of chromosomes 1q, 6q (LATS1), and 9p21 (CDKN2A). Data relating to these variables were compared with survival data in order to model disease-risk groups. Results Extent of surgical resection was a significant determinant of outcome. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas (n=119). Among pathologic factors, only brain invasion was associated with outcome in children with supratentorial ependymomas (n=27). Gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined a three-tier system of disease-risk for posterior fossa tumors. Conclusions Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease-risk. In contrast, risk factors for pediatric supratentorial tumors are limited to subtotal resection and brain invasion.