The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility of epigenetic involvement in pathogenesis. In pursuit of this hypothesis, we took an integrative approach to analyze the methylomes, transcriptomes, and copy number variations in 105 cases of neuroblastoma, complemented by primary tumor- and cell line–derived global histone modification analyses and epigenetic drug treatment in vitro. We found that DNA methylation patterns identify divergent patient subgroups with respect to survival and clinicobiologic variables, including amplified MYCN. Transcriptome integration and histone modification–based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk–associated transcriptional deregulation. Furthermore, in high-risk neuroblastomas, we obtained evidence for cooperation between PRC2 activity and DNA methylation in blocking tumor-suppressive differentiation programs. Notably, these programs could be re-activated by combination treatments, which targeted both PRC2 and DNA methylation. Overall, our results illuminate how epigenetic deregulation contributes to neuroblastoma pathogenesis, with novel implications for its diagnosis and therapy. Cancer Res; 76(18); 5523–37. ©2016 AACR.