In a lot of factors, thermal deformation of motorized high-speed spindle is a key factor affecting the manufacturing accuracy of machine tool. In order to reduce the thermal errors, the reasons and influence factors are analyzed. A thermal error model, that considers the effect of thermodynamics and speed on the thermal deformation, is proposed by using genetic algorithm-based radial basis function neural network. The improved neural network has been trained and tested, then a thermal error compensation system based on this model is established to compensate thermal deformation. The experiment results show that there is a 79% decrease in motorized spindle errors and this model has high accuracy.