Objective To compare the mechanical stability and setup accuracy of different head immobilization systems(HIS) in brain tumor radiotherapy and provide evidence for precise treatment planning. Methods A total of 80 patients underwentg radiotherapy for brain tumors at the Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical University from January 2022 to December 2024 were enrolled. Based on the type of head immobilization system used, patients were divided into three groups: the thermoplastic mask system (TMS) group, the vacuum cushion system (VCS) group, and the stereotactic frame system (SFS) group. All patients underwent computed tomography (CT) simulation positioning before treatment and image-guided correction was performed using the kilovoltage cone-beam computed tomography (kV-CBCT) system built into the accelerator. Translational and rotational errors were recorded to calculate systematic error (Σ), random error (σ), total vector error (TVE), and margin (M). Univariate and multivariate linear regression analyses were performed to identify major influencing factors. Results The translational and rotational errors across all three groups were within acceptable clinical limits. The SFS group was significantly lower than the other two groups in translation, rotation, Σ and σ (all P＜0.05), followed by the VCS group and TMS group. The calculated safety margins showed the same trend. Over treatment fractions, setup deviation slightly increased in the TMS group, remained stable in the VCS group, and was minimal in the SFS group. Regression analysis identified immobilization type and fraction number as the main factors affecting setup error (all P＜0.05). Conclusion Mechanical stability varies among HIS in brain tumor radiotherapy. The SFS provides the best positioning precision and reproducibility, the VCS balances comfort and stability, while the TMS requires frequent image guidance during multi-fraction treatments. The rational selection and standardized use of immobilization systems can significantly enhance the precision and safety of brain tumor radiotherapy.