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Simple Summary: This was a multicenter, single-arm, phase II study comprising two protocol treatments. Patients were enrolled after craniotomy or biopsy and initiated the concurrent phase; oral daily temozolomide concomitant with radiation therapy during the first 6 weeks of treatment. Bevacizumab was intravenously administered every other week. The protocol-defined secondary therapy (i.e., BBP regimen) was given as bevacizumab monotherapy or in combination with other chemotherapeutic agents upon first progression or recurrence until further progression or unacceptable toxicity developed. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. Expression profiling using RNA sequencing identified that Cluster 2, enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab. [ABSTRACT FROM AUTHOR]