Glioblastoma represents the most common malignant primary brain tumor with poor survival rates despite of standard radical treatment, which includes maximal surgical resection and chemo-radiation therapy. Recurrence is widely considered inevitable with almost 100% of patients developing signs of progressive disease 6–10 months following diagnosis [1]. Moreover, the management of recurrent glioblastomas remains tortuous and complex with a median survival time precluded to 6 months [2]. Although microsurgery is often considered in these cases, feasibility remains surrogate to key factors such as the degree of regional infiltration, patients’ performance status, neurological function, and underlying co-morbidity [3]. Systemic treatment is seldom effective at long-term and often associated to toxicity [4], [3]; indeed, only the anti-VEGF monoclonal antibody Bevaczumab has been approved by Food and Drug Administration (FDA) for recurrent disease [5], [6], [7]. Re-irradiation schedules utilizing single fraction stereotactic radiosurgery (SRS), repeat conventional fractionated radiotherapy and hypofractionated stereotactic radiotherapy (HSRT), have also been proposed; yet to this day, there is no clear consensus on the subject [2], [8], [9], [10], [11], [12], [13], [14], [15]. Toxicity to normal brain tissue, which is dose-volume dependent, appears to be the main limiting factor for repeat radiation treatments [16], [17], [18], [19]. In this context, SRS facilitates a more accurate high dose to the target with a rapid dose fall-off at the normal brain tissue as compared to conventional radiation therapy. Nonetheless, SRS also implies collateral cytotoxic effects to peri-lesional healthy tissue; as such, its use is mainly limited to small-sized lesions [20], [21], [22]. Alternatively, HSRT has been shown to overcome this problem, as confirmed by multiple studies; this is possibly due to a set of radiobiological events carefully interacting with the immune system, not necessarily seen on SRS [11], [23], [24], [25], [26]. Extensive evidence highlighting the benefits of Gamma Knife radiosurgery (GKRS) in distinct fractionation setups (SRS or HSRT) can be found in the literature; however, studies on GKRS and recurrent glioblastoma remain scarce [27]. So far, there is no consensus on the use of SRS or other radiation treatment schedules for recurrent glioblastoma. To contribute with the existing data, we investigated the effects of GKRS-based SRS and HSRT on a patient population with recurrent glioblastoma; overall survival (OS), local progression free survival (LPFS), and safety were thoroughly analyzed.