Abstract: During high-temperature service, Cr20Ni80 electrothermal alloy tends to form a large number of vacancy defects, which affects its resistivity and service performance. The effects of Ni vacancies, Cr vacancies and their concentrations on the resistivity of Cr20Ni80 alloy were systematically investigated by combining first-principles calculations with experimental analysis. Based on the nearest-neighbor method and the minimum-energy principle, Cr20Ni80 alloy supercell models containing vacancies were constructed. The formation energy, density of states and band structure of the supercell systems with different vacancy types and concentrations were calculated. The influence of vacancy concentration on the electrical properties of Cr20Ni80 alloy was further verified by X-ray diffraction and resistivity measurements. The results show that the introduction of vacancies reduces the stability of the supercell system, and the stability further decreases with increasing of vacancy concentration. Vacancies narrow the energy range of the conduction band and enhance electron localization, which increases the resistivity of the alloy. Compared with Cr vacancies, Ni vacancies have a weaker effect on the resistivity of the alloy. With the increase of Ni vacancy concentration, the resistivity of the alloy increases continuously; however, as the Cr vacancy concentration increases, the increasing trend of resistivity gradually weakens. In addition, with the increase of quenching temperature, the concentration of supersaturated vacancies retained in the alloy after rapid cooling increases, leading to a further increase in resistivity. The experimental results exhibit good consistency with the first-principles calculation results.