BACKGROUND: There is a clear need to improve the efficiency of therapeutic strategy for patients with newly diagnosed glioblastoma (GBM). The purpose of this study was to evaluate the feasibility of hypofractionated intensity-modulated radiation therapy (IMRT), temozolomide and granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with newly diagnosed GBM. METHODS: Patients were treated with hypofractionated IMRT (15 × 3.5Gy to the high-risk region and 15 × 3.0Gy to the low-risk region), temozolomide (75 mg per square meter of body-surface area per day, from 1 week before the beginning of radiotherapy to the last day of radiotherapy) and GM-CSF [200μg (equivalent to 125 μg/m² calculated dose) subcutaneously injected daily for 2 weeks, starting from the second week of radiotherapy]. The primary endpoint was 6-month progression free survival (PFS). RESULTS: Between June 2016 and Feburary 2020, 41 patients were enrolled. During concomitant chemoradiotherapy, no grade 3 or 4 hematologic toxicities were observed and grade 3 non-hematologic toxicities were documented in 5 patients (12.2 %) due to GM-CSF. All patients completed both radiotherapy and concomitant temozolomide as planned. Only five patients (12.2 %) discontinued concomitant GM-CSF because of toxicity. At a median follow-up of 33.1 months (IQR 23.0-51.2), the 6-month PFS rate was 68.3 % (95 % CI: 54.0-82.6). The median overall survival of all patients was 16.7 months (95 % CI: 10.5-22.9). Compared with pre-GM-CSF, the concentrations of TNF-α (p = 1.9615E-10) and IL-18 (p = 6.8467E-8) were increased after GM-CSF, while the proportion of CD19 (p = 0.000015), the concentrations of IgG (p = 0.000015) and CXCL12 (p = 0.000257) were decreased. CONCLUSIONS: The combination of hypofractionated IMRT, temozolomide and GM-CSF for GBM was feasible and safe. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02663440.