Glioblastomas (GBM) are the most common malignant primary brain tumors in adults and have a dismal prognosis. Patients frequently suffer from local tumor recurrences, with limited therapeutic options. Re-irradiation represents a possible intervention, but given the recent 5th edition of the World Health Organization classification of central nervous system tumors, studies in isocitrate dehydrogenase wild type (IDH-wt) cohorts undergoing a second course of radiotherapy remain limited. Herein, we sought to describe our institutional experience and outcomes after GBM IDH-wt re-irradiation. GBM patients with confirmed IDH-wt status undergoing re-irradiation were included in this single-center, retrospective analysis. A total of 88 patients were analyzed. The median clinical and radiographic follow-up periods were 4.6months and 4.4months, respectively. Most patients had a Karnofsky performance status of at least 80% (n=57). The median biologically effective dose and 2Gy equivalent dose (EQD2) for re-irradiations, assuming an α/β ratio of 10Gy for GBM, were 51.4 and 42.8Gy, respectively. In total, 71 deaths were recorded. The median overall survival (OS) was 8.0months. Multivariable Cox regression of OS revealed a positive influence of gross total resection vs. biopsy or no resection (hazard ratio: 0.43, p=0.02). The median progression-free survival (PFS) was 5.9months. The multivariable Cox regression for PFS did not detect any significant factors. No clear evidence of radiation necrosis was recorded during the available follow-up. However, only a minority (n=4) of patients underwent surgery after re-irradiation, none showing histopathological proof of radiation necrosis. The prognosis for recurrent IDH-wt GBM after re-irradiation is poor. Patients who are amenable and able to undergo re-resection may have a favorable OS. A second course of radiotherapy with a moderate cumulative EQD2 and small- to medium-sized planning target volumes appeared safe regarding the occurrence of radiation necrosis.