Purpose <p>A comparison of acute toxicity between photon and proton radiotherapy (RT) for children undergoing treatment for medulloblastoma.</p> Methods <p>This retrospective multi-institutional cohort study included 96 children &lt; 18 years treated for medulloblastoma in Sweden during 2008–2020. Patients treated with protons (<i>n</i> = 37) and photons (<i>n</i> = 59) were compared regarding acute side effects and radiation dose to intracerebral organs at risk (OARs). Data was collected from a prospectively maintained national database and was supplemented from a retrospective review of medical records. Acute symptoms were graded according to CTCAE (Common Terminology Criteria for Adverse Events), maximum grade occurring during RT and within 2 months after RT. Hematological toxicity was evaluated according to maximum grade and percentual reduction during RT.</p> Results <p>No significant differences in incidence or severity of acute symptoms were observed between proton-RT and photon-RT; grade ≥ 2 fatigue (5.4 vs. 10.2%), headache (2.7 vs. 3.4%), nausea (43.2 vs. 42.4%), dermatitis (5.4 vs. 15.3%), gastrointestinal toxicity (0 vs. 0%), weight loss (10.8 vs. 8.5%). Median percentual reduction (0% vs. -11,25%) in hemoglobin was significantly smaller during proton-RT (<i>p</i> &lt; 0.001). No difference was observed for leucocytes, neutrophiles, or platelets. Absorbed mean dose to intracranial OARs was significantly lower with proton-RT.</p> Conclusion <p>This is one of the largest studies comparing acute side effects of proton-RT and photon-RT including only paediatric medulloblastoma patients. Proton-RT was safe and well tolerated regarding acute side effects. Absorbed dose to intracranial OARs was significantly lower with proton-RT. Further investigations of long-term side effects and cognitive evaluation is needed to show that this will translate into true clinical value for patients.</p>