The flexible dynamic model of spindle system of high speed grinder was constructed to simulate the performance of spindle system under uncertain grinding force, which is more suitable to model the actual working condition. Radial basis function approximation model was used to replace the time consuming simulation model. The approximation model was created by the samples obtained through Latin hypercube experiment design method within the hybrid space,which was formed by the design space and uncertain space. The uncertain optimization method based on interval number was employed to optimize the design of spindle system. After optimizing the key variables of spindle system, the displacement magnitude of grinding wheel’s centroid decreases greatly, which indicates that the quality of grinding becomes better. The respones interval of the optimal design under the uncertainty can be obtained sequentially.