Background: Glioblastoma (GBM) has a very poor prognosis, and the majority of patients die within 2 years of diagnosis. GBMs have high concentrations of vascular endothelial growth factor (VEGF), and the more VEGF, the worse the prognosis. Bevacizumab is a humanized antibody to VEGF and is active in recurrent GBMs. The study aims to improve the survival of newly diagnosed GBM patients by incorporating an anti-angiogenic agent with radiation and temozolomide, and adding a topoisomerase I inhibitor, and an anti-angiogenic agent to temozolomide post-radiation therapy. Methods: Patients received standard radiation and temozolomide at 75 mg/m²/day, with bevacizumab at 10 mg/kg every 14 days beginning a minimum of 28 days post-operatively. Following the completion of radiation therapy, patients received 6-12 cycles of bevacizumab, temozolomide and irinotecan. Each cycle was 28 days. Bevacizumab was given at a dose of 10 mg/kg days 1 and 15, temozolomide 200 mg/m² days 1-5 and irinotecan on days 1 and 15 at 125 mg/m² for patients not on an enzyme inducing anti-epileptic (EIAED) and 340 mg/m² for patients on an EIAED. The statistical design was a goal of 60% overall survival at 16 months. Results: 125 patients were enrolled between 8/07 and 3/09. All the patients have completed therapy. Nine patients had thromboembolic complications (DVT or PE). Two patients had wound dehiscence, one bowel perforation, one secondary AML and two pneumocystis carinii pneumonias (PCP). Seventeen had grade 4 hematologic toxicity requiring dose decrements. There were 4 toxic deaths, one each with a myocardial infarction PCP, PE and sepsis. At a median follow-up of 40 mos, the median overall survival was 20.9 mos, the median progression-free survival was 13.8 mos and the 2-year overall survival was 42.4%. Conclusions: Adding bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide with irinotecan is tolerable and efficacious.