Background Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)–TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double‐blinded, placebo‐controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM. Methods Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6‐month progression‐free survival (PFS). Results After an initial 6‐patient lead‐in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6‐month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4‐14.2 months), median PFS was 4.8 months (95% CI, 3.8‐7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6‐month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8‐10.1 months), median PFS was 4.2 months (95% CI, 3.7‐5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms. Conclusion The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6‐month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental. This phase 2, double‐blinded, placebo‐controlled trial in patients with recurrent glioblastoma (rGBM) through NRG oncology shows that the combination of bevacizumab plus trebananib—an angiopoietin (Ang) inhibitor—does not significantly improve 6‐month progression‐free survival (PFS) rate, PFS, or overall survival for patients with rGBM compared with bevacizumab plus placebo. The Ang1 blocking effects of trebananib may somehow counteract or negate the antitumor effects of the Ang2–vascular endothelial growth factor blockade.