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Background Recent studies have identified that glioblastoma IDH-wild-type (GBM IDH-WT) might be comprised of molecular subgroups with distinct prognoses. Therefore, we investigated the correlation between genetic alterations and survival in 282 GBM IDH-WT patients, to identify subgroups with distinct outcomes. Methods We reviewed characteristics of GBM IDH-WT (2009-2019) patients analyzed by next-generation sequencing interrogating 205 genes and 26 rearrangements. Progression-free survival (PFS) and overall survival (OS) were evaluated with the log-rank test and Cox regression models. We validated our results utilizing data from cBioPortal (MSK-IMPACT dataset). Results Multivariable analysis of GBM IDH-WT revealed that treatment with chemoradiation and RB1-mutant status correlated with improved PFS (HR 0.25 p<0.001 and HR 0.47, p=0.002) and OS (HR 0.24 p<0.001 and HR 0.49, p=0.016). In addition, younger age (<55-years) was associated with improved OS. Karnofsky performance status <80 (HR=1.44, p=0.024) and KDR amplification (HR=2.51, p=0.008) were predictors of worse OS. KDR-amplified patients harbored coexisting PDGFRA and KIT amplification (p<0.001) and TP53-mutations (p=0.04). RB1-mutant patients had less frequent CDKN2A/B and EGFR alterations (p<0.001). Conversely, RB1-mutant patients had more frequent TP53 (p<0.001) and SETD2 (p=0.006) mutations. Analysis of the MSK-IMPACT dataset (n=551) validated the association between RB1 mutations and improved PFS (11.0-months vs. 8.7-months, p=0.009) and OS (34.7-months vs. 21.7-months, p=0.016). Conclusions RB1-mutant GBM IDH-WT is a molecular subgroup with improved PFS and OS. Meanwhile, 4q12 amplification (KDR/PDGFRA/KIT) denoted patients with worse OS. Identifying subgroups of GBM IDH-WT with distinct survival is important for optimal clinical trial design, incorporation of targeted therapies, and personalized neuro-oncological care.