Advanced generation-four (G-IV) nuclear reactor is recognized as an efficient approach that addresses the global energy crisis and environmental pollution. However, existing traditional structural materials cannot comply with the requirements under such extreme environments. Therefore, the innovative design of metallic materials that can bear higher radiation doses and operating temperatures has become the crucial issue for development of advanced nuclear reactors. Recently, distinguished from conventional structural alloys with disordered structures, chemically complex intermetallic alloys (CCIMAs) with ordered crystal structures have attracted considerable attentions owing to a complementary combination of excellent high-temperature mechanical properties, good oxidation resistance, and promising radiation tolerance. Also, it is revealed that simply tailoring the chemical complexity of disorder-structured alloys can efficiently reduce mean free paths of electron and phonon, and then modify the defect dynamics, contributing to enhancing the irradiation tolerance. Meanwhile, order-structured alloys are found to have a low atomic mobility and sluggish lattice diffusion that could increase energy barriers of vacancy and interstitial atoms, thus resulting in an improved radiation resistance. Through combining the intrinsic ordered structures and multiple chemistries, it is expected to achieve extraordinary radiation resistance in CCIMA systems together with superb mechanical properties. Even so, the radiation responses in CCIMAs have never been systematically evaluated, and the underlying mechanism is far from clear. To meet the requirements of high temperature and high irradiation dose of the Gen-IV systems, this proposed research aims to design a novel CCIMA with an ordered L12structure that possesses excellent strength-ductility and outstanding irradiation resistance. With the assistance of the CALPHAD (CALculation of PHAse Diagrams) simulation and thermomechanical processing (TMP), the optimized composition, grain size, and associated mechanical property of the L12-type CCIMAs are carefully engineered and evaluated. Subsequently, the defect evolution and radiation-induced segregation (RIS) behaviors under heavy ion irradiation at elevated temperatures (i.e., 873 K~1173 K) will be systematically investigated. The underlying mechanisms will be further discussed. Eventually, with transmission electron microscopy (TEM) and atom probe tomography (APT), the microstructural stability of this CCIMAs under irradiation and thermal exposure will be characterized. Based on the systematic experimental studies, the mechanisms of irradiation tolerance of the L12-type CCIMAs will be revealed. The successful fulfillment of this proposal will lead to a comprehensive understanding of the irradiation responses of the CCIMAs that is not yet documented, which will provide an effective guideline for the proper design of radiation-resistant CCIMAs for advanced nuclear applications.