Interfacing-System Loss of Coolant Accident (ISLOCA) is a less frequent but extremely serious accident. In this paper, the risk of ISLOCA is studied by using probability safety analysis (PSA) method. The results show that HPR1000 effectively reduces the risk of ISLOCA through targeted design, and the frequency of core damage and large release is less than 1E-08/reactor year. These design measures include the enhanced design pressure and inlet valves interlocking of Residual Heat Remove System, valves configure of Reactor coolant pump high pressure cooler line. This study also quantitatively analyzes the impact of mitigation actions and different design measures on risk. These conclusions can be used for continues design optimization of nuclear power plants. The analytical method established in this study can also be applied to the ISLOCA risk evaluation of other nuclear power plants.