SummaryAimsWe aimed to identify a clinically useful biomarker using DNA methylation‐based information to optimize individual treatment of patients with glioblastoma (GBM).MethodsA six‐CpG panel was identified by incorporating genome‐wide DNA methylation data and clinical information of three distinct discovery sets and was combined using a risk‐score model. Different validation sets of GBMs and lower‐grade gliomas and different statistical methods were implemented for prognostic evaluation. An integrative analysis of multidimensional TCGA data was performed to molecularly characterize different risk tumors.ResultsThe six‐CpG risk‐score signature robustly predicted overall survival (OS) in all discovery and validation cohorts and in a treatment‐independent manner. It also predicted progression‐free survival (PFS) in available patients. The multimarker epigenetic signature was demonstrated as an independent prognosticator and had better performance than known molecular indicators such as glioma‐CpG island methylator phenotype (G‐CIMP) and proneural subtype. The defined risk subgroups were molecularly distinct; high‐risk tumors were biologically more aggressive with concordant activation of proangiogenic signaling at multimolecular levels. Accordingly, we observed better OS benefits of bevacizumab‐contained therapy to high‐risk patients in independent sets, supporting its implication in guiding usage of antiangiogenic therapy. Finally, the six‐CpG signature refined the risk classification based on G‐CIMP and MGMT methylation status.ConclusionsThe novel six‐CpG signature is a robust and independent prognostic indicator for GBMs and is of promising value to improve personalized management.