Glioblastoma is the most common, malignant adult primary tumor with dismal patient survival, yet the molecular determinants of patient survival are poorly characterized. Global methylation profile of GBM samples (our cohort; n=44) using high-resolution methylation microarrays was carried out. Cox regression analysis identified a 9-gene methylation signature that predicted survival in glioblastoma patients. A risk-score derived from methylation signature, predicted survival in univariate analysis in our and TCGA cohort. Multivariate analysis identified methylation risk-score as an independent survival predictor in TCGA cohort. Methylation risk-score stratified the patients into low-risk and high-risk groups with significant survival difference. Network analysis revealed an activated NFkB pathway association with high-risk group. NFkB inhibition reversed glioma chemoresistance and RNA interference studies identified IL6 and ICAM1 as key NFkB targets in imparting chemoresistance. Promoter hypermethylation of NPTX2, a risky methylated gene, was confirmed by bisulfite sequencing in GBMs. GBMs and glioma cell lines had low levels of NPTX2 transcripts which could be reversed upon methylation inhibitor treatment. NPTX2 overexpression induced apoptosis, inhibited proliferation and anchorage-independent growth and rendered glioma cells chemosensitive. Further, NPTX2 repressed NFkB activity by inhibiting AKT through a p53-PTEN dependent pathway, thus explaining the hypermethylation and downregulation of NPTX2 in NFkB activated high-risk GBMs. Taken together, a 9-gene methylation signature was identified as an independent GBM prognosticator and could be used for GBM risk stratification. Pro-survival NFkB pathway activation characterized high-risk patients with poor prognosis indicating it to be a therapeutic target.