Glioblastoma (GBM) is the frequently occurring and most aggressive form of brain tumors. In the study, we constructed an immune-related gene pairs (IRGPs) signature to predict overall survival (OS) in patients with GBM. We established IRGPs with immune-related gene (IRG) matrix from The Cancer Genome Atlas (TCGA) database (Training cohort). After screened by the univariate regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis, IRGPs were subjected to the multivariable Cox regression to develop an IRGP signature. Then, the predicting accuracy of the signature was assessed with the area under the receiver operating characteristic curve (AUC) and validated the result using the Chinese Glioma Genome Atlas (CGGA) database (Validation cohorts 1 and 2). A 10-IRGP signature was established for predicting the OS of patients with GBM. The AUC for predicting 1-, 3-, and 5-year OS in Training cohort was 0.801, 0.901, and 0.964, respectively, in line with the AUC of Validation cohorts 1 and 2 [Validation cohort 1 (1 year: 0.763; 3 years: 0.786; and 5 years: 0.884); Validation cohort 2 (1 year: 0.745; 3 years: 0.989; and 5 years: 0.987)]. Moreover, survival analysis in three cohorts suggested that patients with low-risk GBM had better clinical outcomes than patients with high-risk GBM. The univariate and multivariable Cox regression demonstrated that the IRGPs signature was an independent prognostic factor. We developed a novel IRGPs signature for predicting OS in patients with GBM.