This study reported different patterns of CNS radiotoxicity, including radiation-induced leukoencephalopathy (RIL), brain tissue necrosis (TN), and cerebral microbleeds (CMB) in patients with WHO grade 2-3 gliomas treated with proton (PRT) or photons (XRT). Thirty-four patients (XRT = 17 vs PRT = 17) matched by demographic/clinical criteria were analyzed. Radiotoxicity was assessed for 3 years post RT. The study found that 1) both groups developed moderate-to-severe RIL (62% XRT, 71% PRT) within 3 years; XRT was associated with persistent RIL increases in the contralesional hemisphere, whereas contralesional hemispheric RIL plateaued with PRT at 1-year post-RT; 2) TN rates were greater with PRT (6% XRT vs 18% PRT); 3) CMB prevalence was similar (76% XRT, 71% PRT); XRT correlated with greater contralesional hemispheric CMB burden (27% XRT, 17% PRT, P = .026), whereas PRT-specific CMB clustered at the radiation field margin (P = .002).