In this paper, a nonisothermal fluid-structure interaction mathematical model for the piston/cylinder interface leakage is presented. Full account is taken of the piston eccentricity, elastic deformations of the piston pair, the nonisothermal flow in the interface, and the physical properties of the fluid such as the pressure-viscosity and temperature-viscosity effects. The numerical method for the solution of the model is given, which can simultaneously solve for the fluid pressure distribution and leakage rate in the interface. The model is validated by comparing the calculated leakage rates with the measurements. Results show the good accuracy of the model. The impacts of parameters such as the piston diameter, the initial clearance between the piston pair, and the piston velocity on the leakage rate are discussed. Some of the conclusions provide good guidance for the design of high-pressure fuel pumps.