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Previous studies have demonstrated possible differences in glioblastoma (GBM) survival attributable to ethnicity. The goal of this study was to quantify oncogenic differences and evaluate the overall survival (OS) and progression-free survival (PFS) differences in GBM patients across race/ethnicity using both population-based surveillance and institutional data sets from the United States (US) and Mexico. Retrospective cohort study comprising the Texas Cancer Registry (TCR, n = 4134) and referral institutions located in US (n = 254) and Mexico (n = 47) were evaluated. Primary outcomes include OS and PFS. Oncogenic differences attributable to ethnicity were assessed. IDH1/IDH2 status was evaluated by sequencing in US and Mexico samples. Kaplan-Meier and Cox proportional hazards regression for survival analysis. A total of 4134 GBM patients were identified from the TCR data set, ethnicity comparison demonstrated that Hispanic patients were diagnosed at a significantly younger age compared to non-Hispanic white patients (NHW) (median: 58 vs. 62, P < 0.001) and had improved OS (hazard ratio: 0.82, P < 0.001). In the oncogenic analysis, we observed a significant enrichment of IDH1/IDH2 mutations in Mexican Hispanic patients compared to US Hispanic patients (29.8% vs. 7.9%, P = 0.012); IDH2 mutations drove this difference. Post-progression survival was significantly shorter in patients from Mexico than US (3.0 vs. 11.4 months; P < 0.001), while OS remained similar. IDH2 mutations are more prevalent in Mexican Hispanic individuals compared to US individuals and may be a crucial contributor to the previously reported survival benefit of Hispanic individuals in large population databases. These findings are critical for both screening of IDH2 mutations and targeted interventions in GBM. [ABSTRACT FROM AUTHOR]