Background. Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior tochemoradiationinpatientswithunresectable,subtotally resected, and/or multifocal GBM. Methods. Patients received up to 4 cycles of TMZ at 200 mg/m2 per day on days 1–5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m2 or 340 mg/m2 depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity.The primary endpointwas tumor response rate,with a goal of 26% or greater. Results. Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial respons!e, 25 (61.0%) had stable disease,and2(4.9%)hadprogression;5patientswerenotassessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2–13.5months). Conclusion. Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.