X-ray induced photodynamic therapy (X-PDT) circumvents the poor penetration depth of conventional PDT with minimal radio-resistance generation. However, conventional X-PDT typically requires inorganic scintillators as energy transducers to excite neighboring photosensitizers (PSs) to generate reactive oxygen species (ROS). Herein, a pure organic aggregation-induced emission (AIE) nanoscintillator (TBDCR NPs) that can massively generate both type I and type II ROS under direct X-ray irradiation is reported for hypoxia-tolerant X-PDT. Heteroatoms are introduced to enhance X-ray harvesting and ROS generation ability, and AIE-active TBDCR exhibits aggregation-enhanced ROS especially less oxygen-dependent hydroxyl radical (HO•- , type I) generation ability. TBDCR NPs with a distinctive PEG crystalline shell to provide a rigid intraparticle microenvironment show further enhanced ROS generation. Intriguingly, TBDCR NPs show bright near-infrared fluorescence and massive singlet oxygen and HO•- generation under direct X-ray irradiation, which demonstrate excellent antitumor X-PDT performance both in vitro and in vivo. To the best of knowledge, this is the first pure organic PS capable of generating both 1 O2 and radicals (HO•- ) in response to direct X-ray irradiation, which shall provide new insights for designing organic scintillators with excellent X-ray harvesting and predominant free radical generation for efficient X-PDT.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.