Background: Prognosis for recurrent glioblastoma (GBM) remains poor with median survival between 3 to 6 months. Use of anti-vascular endothelial growth factor inhibitor, bevacizumab (BEV), has advanced this area of research, but continued studies have focused on whether the addition of other chemotherapies can improve efficacy in recurrent GBM. Vorinostat, a small molecule inhibitor of histone deactylase (HDAC), has anti-tumor activity directly through HDAC inhibition and indirectly by promoting anti-angiogenesis. Its good oral bioavailability and favorable toxicity profile make it a promising additive agent to standard therapy. Thus, we evaluated the efficacy of vorinostat in combination with BEV and daily temozolomide (TMZ) in recurrent GBM. Methods: This was a phase I/II open-label, single arm study in recurrent GBM patients. Primary endpoint was 6-month progression free survival (PFS). Secondary endpoints were safety/tolerability, radiographic response, PFS, and overall survival of recurrent GBM patients treated with BEV plus daily TMZ and vorinostat. Chief eligibility criteria included age ≥ 18 years, KPS ≥ 70, time interval ≥ four weeks from previous treatment, and maximum of 2 prior progressions. Dosing regimen was as follows: BEV 10 mg/kg IV every two weeks, TMZ 50 mg/m² po daily, and vorinostat 400 mg po for 7 days on then 7 days off in a 28 day cycle. Results: 46 recurrent GBM patients were enrolled with 42 of those patients receiving a vorinostat dose of 400 mg. Most common grade 2 and above toxicities were leukopenia (36%), neutropenia (29%), fatigue (24%), and thrombocytopenia (19%). Serious toxicities included 4 grade 4 toxicities (grade 4 hyperglycemia, pulmonary embolism, bowel perforation and intracranial hematoma) and 1 patient expired on day of informed consent due to pulmonary embolism (grade 5). With a median follow-up of 11.3 months (95% CI: 10.1, 13.1 months), the 6-month PFS was 52.4% (95% CI: 36.4%, 66.1%). Best radiographic responses were 2 complete responses, 17 partial responses, 20 stable responses, and 1 radiographic progression. Conclusions: In summary, combination of BEV, daily TMZ, and vorinostat has promising efficacy on recurrent GBM with reasonable toxicity/safety.