X-ray-based radiotherapy is a standard treatment for brain tumors. However, it is associated with systemic effects like lymphopenia that correlates with poor prognosis. Protontherapy has emerged as a new strategy, given that its ballistic properties (lower entry dose and lack of an exit dose) are exploited to spare healthy brain tissue and reduce side effects caused by systemic inflammation. We investigated how protons could spare circulating leukocytes relative to x-rays and if observed effects could be mediated by ballistic, biologic effects or both. Tumor-free C57BL/6 mice model was used for x-ray or proton brain irradiation with 20Gy. Groups were also defined according to irradiation volume (whole-brain or hemisphere). Total peripheral blood was withdrawn at various time points, at which lymphoid with myeloid subpopulations were analysed using flow cytometry. It confirmed acute and severe radiation-induced lymphopenia with depletion of nearly 50% CD3+, CD4+, CD8+, B and NK cells after x-rays. We showed a conservative effect of protons by the decrease of only 15% lymphocytes after whole-brain exposure. Further investigations like brain and spleen in vivo imaging, CD68/Iba1 and GFAP immunostaining quantifications in brain and cytokine/chemokine assays were performed to better explain the differences observed between both beams. The inclusion of a GL261 tumor-bearing mice model and the use of a x-ray-lateral beam challenged our understanding of the underlying mechanisms of lymphopenia. Our data demonstrated that protons differs from x-rays in terms of its ballistic and biologic effects and is conservative for lymphocytes, opening the avenue for protontherapy with immunotherapy combination.