The treatment of hypoxic tumours continues to be one of the main challenges for radiation therapy. Minibeam radiation therapy (MBRT) shows a highly promising reduction of to-xicity in normal tissue, so that very heavy ions, such as Neon (Ne) or Argon (Ar), with extremely high LET, might become applicable to clinical situations. The high LET in the target would be unrivalled to overcome hypoxia, while MBRT might limit the side effects normally preventing the use of those heavy ions in a conventional radiotherapeutic setting. The work reported in this manuscript is the first experimental proof of the remarkable reduction of normal tissue (skin) toxicities after Ne MBRT irradiations as compared to conventional Ne irradiations. This result might allow for a renewed use of very heavy ions for cancer therapy. (1) Background: among all types of radiation, very heavy ions, such as Neon (Ne) or Argon (Ar), are the optimum candidates for hypoxic tumor treatments due to their reduced oxygen enhancement effect. However, their pioneering clinical use in the 1970s was halted due to severe side effects. The aim of this work was to provide a first proof that the combination of very heavy ions with minibeam radiation therapy leads to a minimization of toxicities and, thus, opening the door for a renewed use of heavy ions for therapy; (2) Methods: mouse legs were irradiated with either Ne MBRT or Ne broad beams at the same average dose. Skin toxicity was scored for a period of four weeks. Histopathology evaluations were carried out at the end of the study; (3) Results: a significant difference in toxicity was observed between the two irradiated groups. While severe da-mage, including necrosis, was observed in the broad beam group, only light to mild erythema was present in the MBRT group; (4) Conclusion: Ne MBRT is significantly better tolerated than conventional broad beam irradiations.