Abstract Author Summary Background. Patients with a newly diagnosed glioblastoma multiforme (GBM) have a high risk of recurrent disease with a dismal outcome despite intensive treatment of sequential surgery and chemoradiotherapy with temozolomide (TMZ), followed by TMZ as a single agent. Bevacizumab (BV) may increase response rates to chemotherapy in the recurrent treatment setting of GBM. We hypothesized that a neoadjuvant treatment strategy for patients with newly diagnosed GBM using chemoradiotherapy plus BV would improve resectability and thus survival. We performed a phase II trial of the treatment strategy of BV plus chemoradiation to determine the safety of this combination in patients who had already undergone primary surgery for their GBM. Methods. After a biopsy (6 patients) or a resection (13 patients) of a newly diagnosed GBM, 19 patients received radiotherapy (30 fractions of 2 Gy) in combination with daily TMZ 75 mg/m2 and BV 10 mg/kg on days 1, 14, and 28, followed by 6 monthly cycles of TMZ 150–200 mg/m2 on days 1–5. Results. The overall response rate was 26%. Three patients had a complete response after resection, and in two patients, a complete response after resection followed by chemoradiation plus BV was seen. No grade 3–4 toxicities were observed during combination treatment. The median progression-free survival was 9.6 months (95% confidence interval [CI]: 4.3–14.4 months). The median overall survival was 16 months (95% CI: 8.1–26.3 months), similar to a matched control group that received standard chemoradiotherapy from our institution. Conclusion. Combination of bevacizumab with radiotherapy and TMZ is safe and feasible in patients with newly diagnosed GBM, but because of low response rates, this treatment strategy does not favor a neoadjuvant approach.