The error items and topological structure of the 5-axis machine tool were analyzed, and the coordinate transformation matrix with and without errors when the servo axis moving were given. On this basis, the volumetric comprehensive error calculation method for the 5-axis machine tool was given. The volumetric comprehensive error decoupling algorithm for 5-axis machine tool was given based on the differential transform principle of multibody kinematics. Taking the RTTTR type 5-axis machine tool as an example, the actual comprehensive error decoupling and compensation were calculated by using MATLAB. The results show that the decoupling algorithm is correct.