Purpose <p>Diffusing alpha-emitters Radiation Therapy (“Alpha DaRT”) is a new cancer treatment modality that employs radium-224-loaded metal sources implanted in solid tumors to disperse alpha-emitting atoms within a therapeutic “kill-zone” of a few millimeters around each source. Preclinical studies have demonstrated tumor growth delay in various cancer types, including glioblastoma multiforme, and the method is used in clinical trials for patients with skin and head and neck cancer. This study aims to assess the safety and feasibility of implementing Alpha DaRT for brain tumor treatment in a large animal model.</p> Methods <p>Alpha-DaRT sources were delivered via image-guided stereotactic implantation into both hemispheres of eight swine. 1–3 layers of radial deployment of 7 sources were delivered through a single penetration point into each hemisphere. A 90-day follow-up period included clinical evaluation, brain MRI, head CT, blood, CSF, urine, and feces sampling, and an analysis of source location over time. Brain tissue pathology was performed on termination.</p> Results <p>Alpha-DaRT sources were reproducibly and efficiently delivered to the brain cortex and subcortex. No unexpected abnormalities were detected in blood or CSF samples. MRI and CT scans revealed no evidence of major bleeding or infection. Measurements of ²¹²Pb in blood and CSF exhibited the expected exponential decay from day 7 to day 14 post-source implantation. Minimal spatial and temporal movements of the sources were noted. Histopathological analysis demonstrated locally confined findings in brain parenchyma in a very close proximity to the sources.</p> Conclusion <p>Alpha<b>-</b>DaRT sources can be safely delivered into a large animal brain using image-guided stereotactic implantation. These findings support further exploration of Alpha DaRT as a potential treatment modality for brain tumors.</p>