BACKGROUND: Management of recurrent glioblastoma (rGBM) after standard initial therapy remains one of the most difficult challenges in oncology. Prior use of salvage stereotactic radiosurgery (SRS) for rGBM often involved maximum prescription doses defined by RTOG 90-05. We performed a prospective Phase I study to evaluate the safety of dose escalation when SRS was performed together with bevacizumab. METHODS: Patients with recurrent, histologically proven GBM were included in this Phase I trial. All patients had completed conventional chemoradiation, and had a unifocal enhancing mass with maximum diameter between 2 and 3 cm. Patients received a single dose of Bevacizumab (10mg/kg) followed within 10-14 days by SRS. SRS dose escalation was performed with a 3 + 3 design, starting at 18 Gy, the RTOG 90-05 maximum tolerated dose, and escalated by 2 Gy for each cohort, with a planned maximum of 3 cohorts. The MRI obtained before administration of bevacizumab was used for SRS planning. Patients were continued on a conventional schedule of bevacizumab following SRS. RESULTS: Nine patients were enrolled. Mean duration between bevacizumab and SRS was 12.4 days (10-15). There were no grade 3 or higher toxicities associated with SRS treatment in any dosing cohort. The study was completed after the third patient was treated in the 22 Gy cohort. The median starting tumor volume was 4.54 cm3 (2.1-8.8). The mean volume decrease of the enhancing focus before administration of bevacizumab and at the time of SRS was 1.868 cm3 (95%CI: -0.420–4.156, p-value = 0.103). The median progression free survival after SRS was 7.5 m (95% CI: 3.7–11.2). CONCLUSION: Bevacizumab prior to SRS for recurrent GBM permitted safe SRS dose escalation to 22 Gy. Efficacy of this higher SRS dose should be evaluated in a Phase II trial.