Background: In glioblastoma (GBM), tumor progression occurs mainly within the irradiated tumor volume. To address this challenge, a radiosensitization strategy with intravenous gadolinium-based theranostic nanoparticles (AGuIX) is being explored in the NANO-GBM phase1b/2R trial (NCT04881032). Here, we present the results of the phase 1b part, which is the first-in-human use of these nanoparticles with radiotherapy and chemotherapy for the treatment of newly diagnosed GBM. Material and Methods: Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed GBM, with incomplete resection (biopsy or partial surgery). The phase 1b part was a dose escalation approach (Time-to-event Continuous Reassessment Method) with three dose levels: 50, 75, and 100 mg/kg. Patients were treated with RT (60 Gy), and concomitant and adjuvant TMZ, and 4 injections of AGuIX (D-3/-7, D1, D8, and D15). Dose-limiting-toxicity (DLT) was defined as any grade 3–4 adverse event (CTCAE v5.0), excluding alopecia, nausea, and rapidly controlled vomiting. Pharmacokinetic (PK), and biodistribution based on MRI were evaluated. Results: Between March 2022 and March 2023, eight patients were enrolled: 1 at 50 mg/kg, 1 at 75 mg/kg, and 6 at 100 mg/kg. All patients received the four AGuIX injections. Only one patient experienced a DLT (at 100 mg/kg): a grade 3 lymphopenia (related to TMZ). The RP2D of AGuIX was determined as 100 mg/kg. AGuIX mean AUC increased with dose. Regions of GBM with moderate (36–123 µM), and high (123–291 µM) or very high (>291 µM) AGuIX concentrations accounted in average for 38.7 and 26.8 %, respectively. Conclusion: These results confirm the lack of AGuIX-related toxicity and the widespread dispersion of nanoparticles throughout GBM. This supports progression to the randomized phase 2 part, utilizing an RP2D of AGuIX of 100 mg/kg (4 injections)