Background: Radiosurgery is performed with a diversity of instruments relying usually either on a stereotactic frame or a mask for patient head fixation. Comfort and safety efficacy of the 2 systems have never been rigorously evaluated and compared. Material and Method: Between February 2016 and January 2017, 58 patients presenting with nonsmall cell lung cancer brain metastases have been treated by Gamma Knife radiosurgery (GKS) with random use of a frame or a mask for fixation were included patients older than 18, with <5 brain metastases (at the exclusion of brainstem and optic pathway’s locations) and no earlier history of radiotherapy. The primary outcome measure was the pain scale assessment (PSA) at the beginning of the GKS procedure. Results: The PSA at the beginning of the GKS procedure was not different between the 2 groups. The PSA at the day before GKS, before magnetic resonance imaging, just after frame application, and the day after radiosurgery (departure) has shown no difference between the 2 groups. At the end of the radiosurgery itself (just after frame or mask removal) and 1 h after, the mean pain scale was higher in patients treated with the frame (p < 0.05 and p < 0.001, respectively) but 2 patients were not able to tolerate the mask discomfort and had to be treated with frame. Tumor control and morbidity probability were demonstrated to be no difference between the 2 groups in this population of patients with BM not in highly functional area. The median of the extra dose to the body due to the cone-beam computed tomography was 7.5 mGy with a maximum of 35 mGy in patients treated with a mask fixation (null in the others treated with frame). Mask fixation was associated to longer treatment time although the beam on time was not different between the 2 groups. Conclusion: In selected patients, with brain oligo-metastases out of critical location, single-dose mask-based GKS can be done with a comfort and a safety efficacy comparable to frame-based GKS. There seems to be no clear patient data that confirm the value of the mask system with regards to comfort.