A nickel-base high-temperature alloy (Ni-17Mo-7Cr) has been characterized by nanoindentation and transmission electron microscopy to determine the changes of nanoindentation hardness and microstructural evolution under ion irradiation. Ion irradiation experiments for bulk and thin-foil specimens of Ni-17Mo-7Cr alloy were carried out at room temperature, up to 6.6 dpa, by 7 MeV Xe 26+ and 1 MeV Xe 20+ ions, respectively. The continuous stiffness measurement (CSM) with a diamond Berkovich indent was used to measure the depth profile of hardness. Nanoindentation results for bulk specimens showed an evident ion irradiation induced hardening phenomenon, and the nanoindentation hardness increases with increasing ion dose. High number density of nano-scale black spots and linear-like defects were observed in thin-foil specimens irradiated at 0.33 and 6.6 dpa, respectively. High-resolution transmission electron microscopy images revealed that the black spots were nanoscale solute clusters and dislocation loops, while the linear-like defects were found to be Ni, Mo and Cr-enrichment regions by using the highangle annular dark field-scanning transmission electron microscope. The ion irradiation induced defects can be responsible for the hardening of Ni-17Mo-7Cr alloys.