Background: Despite therapeutic advances in standard of care (SOC), glioblastoma (GBM) remains a devastating disease with a dismal prognosis. In patients with recurrent GBM, bevacizumab (BEV) has demonstrated activity, as measured by objective response rate (ORR) and 6-month progression free survival (PFS), compared with historical controls. The addition of BEV to SOC may add clinical benefit and provide a treatment advantage for patients with newly diagnosed GBM. Methods: In this randomized, double-blind, placebo (PLA)-controlled, multicenter trial, patients ≥18 years with newly diagnosed, histologically confirmed supratentorial GBM will receive SOC radiotherapy (RT; 2 Gy 5 days/wk for 6 wks) and temozolomide (TMZ; 75 mg/m2/day oral) with biweekly BEV or PLA (10 mg/kg intravenous). After completion of RT and a 28-day TMZ-free period, patients will receive TMZ for 5 days every 4 wks (150 mg/m2/day daily, with potential to escalate to 200 mg/m2/day) and biweekly BEV or PLA for 6 cycles or until unacceptable toxicity or disease progression (PD). Subsequently, patients will receive single-agent BEV or PLA (15 mg/kg every 3 wks) until unacceptable toxicity or PD. Co-primary endpoints are investigator-assessed PFS and overall survival. Secondary endpoints are independent radiology review-assessed PFS, 1- and 2-year survival rates, safety, and health-related quality of life. Exploratory endpoints include ORR; duration of response; corticosteroid use; and correlative analyses of biomarkers with efficacy. The protocol was amended in January 2010 to include additional measures of clinical benefit, including the following exploratory endpoints: neurocognitive function, signs and symptoms of disease, Karnofsky performance score, and patterns of PD. First patient was randomized June 29, 2009. The Data Monitoring Committee reviewed the trial on January 19, 2011 and recommended that it continue as planned.