Abstract: The anti-irradiation performance of C276 alloy which is one of candidate materials for the fuel cladding was studied. The samples of C276 alloy were irradiated by multiple ion beams with H, He and Si ions and the test samples before and after irradiation were studied with nano-hardness instrument, transmission electron microscope and Raman imaging instrument. The results show that under the multi-beam ion irradiation, C segregation and dislocation loop hardening occur in irradiation damage region; under the single ion beam irradiation with either H or He, the depth corresponding to the peak of nano-hardness and intensity of carbon peak in Raman spectra is 3.5 μm for He and 35.0 μm for H, and the carbon peak red-shift takes place, about which the test results agree well with the simulation calculation results. It can be concluded that irradiation-induced hardening of C276 alloy arises from co-effects of irradiation-induced segregation and possible dislocation loop hardening.