Although previous studies have documented a significant risk of intellectual loss after treatment for childhood medulloblastoma (MED), the pathophysiology underlying this process is poorly understood. The purpose of this study was to test the hypotheses that (1) patients treated for MED in childhood have reduced volumes of normal white matter (NWM) related to their treatment with craniospinal irradiation with or without chemotherapy, and (2) deficits in NWM among patients surviving MED can at least partially explain deficits in their intellectual performance. Eighteen pediatric patients previously treated for MED were matched on the basis of age at the time of evaluation to 18 patients previously treated for low-grade posterior fossa tumors with surgery alone (mean difference, 3.7 months). Evaluations were conducted with age-appropriate neurocognitive testing and quantitative magnetic resonance imaging by using a novel automated segmentation and classification algorithm constructed from a hybrid neural network. Patients treated for MED had significantly less NWM (p < 0.01) and significantly lower Full-Scale IQ values than those treated for low-grade tumors (mean, 82.1 vs 92.9). In addition, NWM had a positive and statistically significant association with Full-Scale IQ among the patients treated for MED. We conclude that irradiation- or chemotherapy-induced destruction of NWM can at least partially explain intellectual and academic achievement deficits among MED survivors.