Background: Intraoperative balloon electronic brachytherapy (IBEB) may provide potential benefit for local control of recurrent cerebral glioblastomas (GBMs). Methods: This is a preliminary report of an open-label, prospective, comparative cohort study conducted in two neurosurgical centers with ongoing follow-up. At recurrence, patients at one center (n = 15) underwent re-resection with IBEB while, at the second center (n = 15), control subjects underwent re-resection with various accepted second-line adjuvant chemoradiotherapy options. A comparative analysis of overall survival (OS) and local progression-free survival (LPFS) following re-resection was performed. Exploratory subgroup analysis based on postoperative residual contrast-enhanced volume status was also done. Results: In the IBEB group, median LPFS after re-resection was significantly longer than in the control group (8.0 vs. 6.0 months; log rank x2 = 4.93, P = 0.026, P < 0.05). In addition, the median OS after second resection in the IBEB group was also significantly longer than in the control group (11.0 vs. 8.0 months; log rank x2 = 4.23, P = 0.04, P < 0.05). Conclusion: These hypothesis-generating results from a small cohort of subjects suggest putative clinical benefit in OS and LPFS associated with maximal safe re-resection of recurrent GBM with IBEB versus re-resection and standard adjuvant therapy, a hypothesis that deserves further testing in an appropriately powered clinical trial. © 2021 Scientific Scholar. All rights reserved.