Background: The dismal overall survival (OS) prognosis of glioblastoma, even after trimodal therapy, can be attributed mainly to the frequent incidence of intracranial relapse (ICR), which tends to present as an in-field recurrence after a radiation dose of 60 Gray (Gy). In this study, molecular marker-based prognostic indices were used to compare the outcomes of radiation with a standard dose versus a moderate dose escalation. Methods: This retrospective analysis included 156 patients treated between 2009 and 2016. All patients were medically fit for postoperative chemoradiotherapy. In the dose-escalation cohort a simultaneous integrated boost of up to 66Gy (66Gy RT) within small high-risk volumes was applied. All other patients received daily radiation to a total dose of 60Gy or twice daily to a total dose of 59.2Gy (60Gy RT). Results: A total of 133 patients received standard 60Gy RT, while 23 received 66Gy RT. Patients in the 66Gy RT group were younger (p<0.001), whereas concomitant temozolomide use was more frequent in the 60Gy RT group (p<0.001). Other intergroup differences in known prognostic factors were not observed. Notably, the median time to ICR was significantly prolonged in the 66Gy RT arm versus the 60Gy RT arm (12.2 versus 7.6months, p=0.011), and this translated to an improved OS (18.8 versus 15.3months, p=0.012). A multivariate analysis revealed a strong association of 66Gy RT with a prolonged time to ICR (hazard ratio=0.498, p=0.01) and OS (hazard ratio=0.451, p=0.01). These differences remained significant after implementing molecular marker-based prognostic scores (ICR p=0.008, OS p=0.007) and propensity-scored matched pairing (ICR p=0.099, OS p=0.023). Conclusion: Radiation dose escalation was found to correlate with an improved time to ICR and OS in this cohort of glioblastoma patients. However, further prospective validation of these results is warranted.