The flexible bearing is usually connected to the cam with an interference fit in harmonic reducers. Studies show that interference fit can cause changes in the structural parameters of the bearing and lead to changes in the service performance of the bearing and its supporting system. This paper proposes a general simulation method to investigate the influence of interference fit in harmonic reducers with the concept of the equivalent interference for non-circular fit between the flexible bearing and cam. Then, the four steps based on the sequential assembling and loading process are designed to ensure assembly concentricity and simulation convergence. The analysis results indicate that appropriately increasing the equivalent interference can improve the service life of the flexspline without degrading the meshing performance and, at the same time, increase the number of loaded balls to make the operation of the harmonic reducer more stable. Moreover, an optimal equivalent interference can be designed to ensure the harmonic reducer operates at its best, where the number of loaded balls and the maximum Mises stress of the inner ring appear inflection point, and the number of meshing tooth pairs reaches the maximum.