Background: Glioblastoma multiforme (GBM) is an extremely aggressive cerebral tumor with poor prognosis. The majority of patients relapse after the initial surgery plus adjuvant radiation and chemotherapy. In case of recurrence there is no established standard therapy. The optimal techniques for salvage re-irradiation are unclear, so that procedure poses a challenge. In contrast to traditional external beam radiotherapy (EBRT) intra-operative radiotherapy (IORT) may improve patient’s outcome at the cost of minimal side effects and short treatment duration. Methods: A total of 30 patients were treated with recurrent GBM between August 2016 and June 2019. All patients underwent maximal safe resection; patients were divided into IORT and EBRT groups. 15 patients were included in each group with similar clinical characteristics. All patients in IORT group underwent maximal safe microsurgical resection with subsequent intraoperative balloon electronic brachytherapy (IBEB) and no further adjuvant treatment. IBEB was performed using Axxent electronic brachytherapy device (Xoft Electronic Brachytherapy (eBx) System, USA. Patients in EBRT group underwent same surgery followed by external beam radiotherapy. Contrast-enhanced brain MRI with perfusion was performed within 24 hours of surgery +/- brain PET-CT with 18-FDOPA and then every 3 months. Both groups were also assigned to subgroups (≤ 2.5cm3 and > 2.5cm3) based on post-operative contrast-enhancing volume (POCEV). Median overall survival (OS) since diagnosis and local progression-free survival (locPFS) following the second surgery were analyzed. Possible toxicities and prognostic factors were also evaluated. Results: Median OS was 27 months in IORT group and 21 months in EBRT group. The locPFS range between 3.5 to 39 months in IORT group and only 2 to 10 months in group with EBRT. Kaplan-Meier OS curves in patients with POCEV ≤ 2.5cm3 showed more favorable outcomes for patients in the IORT group (p < 0.05). In patients with POCEV > 2.5cm3 the median OS was 17 months in IORT group and 13.5 months in EBRT group. Conclusions: IORT of recurrent GBM is feasible and provides encouraging local progression-free and overall survival; no high-grade radiation induced toxicities occur and further studies to establish this method are mandatory. The toxicity profile of additional IBEB was manageable. Maximal safe microsurgical resection is the most important prognostic factor and could determine the effectiveness of post-surgical IBEB.