Background: The prognosis for newly-diagnosed GBM is dismal. The addition of temozolomide to radiation therapy improved the median overall survival (OS) to 14.6 months (mos). GBM’s have the highest levels of vascular endothelial growth factor (VEGF). Hypoxia inducing factor-1 alpha (HIF-1 alpha) is an important regulator of VEGF, and topotecan may inhibit HIF-1 alpha. Methods: We performed a phase II trial in newly diagnosed GBM by adding bevacizumab and topotecan to standard therapy. 80 newly diagnosed GBM patients were enrolled between January 2010 and January 2011. Patients received standard radiation therapy and temozolomide. Bevacizumab at 10 mg/kg every 14 days was added a minimum of 4 weeks post-op. Two weeks after radiation therapy was completed, 12 monthly cycles of temozolomide at 150 mg/m² /d days 1-5, oral topotecan at 1.5 mg/m² for patients not on an enzyme inducing anti-epileptic drug (EIAED) and 2.0 mg/m² for patients on an EIAED days 2-6, and bevacizumab at 10 mg/kg on days 1 and 15. Results: The addition of bevacizumab to standard radiation therapy and daily temozolomide was safe. Of the 80 patients, 76 completed radiation therapy. Four patients did not complete radiation, two with clinical decline, one each with a bone flap infection, and a pulmonary embolus. Fifteen patients came off study for toxicity, five with recurrent grade IV thrombocytopenia, three with grade III fatigue, two each with grade 2 CNS hemorrhage, and wound dehiscence requiring surgery and one each with GI perforation, pulmonary embolism and an aortic thrombus. Of the 80 patients, 56 have progressed and 37 have died. The median progression-free survival (PFS) and OS are 11.1 mos (95% CI: 9.4-13.6) and 17.2 mos (95% CI: 15.2) at a median follow-up of 18.4 months. The two year OS is 45.3%. Conclusions: The addition of bevacizumab to temozolomide and radiation followed by temozolomide, bevacizumab and oral topotecan is tolerable. The median PFS and OS are encouraging. The randomized phase III trials with bevacizumab for newly diagnosed GBM patients are essential.