The frame of a low-speed electric vehicle was treated as the research object in the paper. The fatigue load of the frame was analyzed with multi-body dynamics method and the fatigue life of frame was analyzed with the nominal stress method. Firstly, the multi-body dynamics model of the vehicle was established and the multi-body dynamics simulation was carried out to simulate the condition where the vehicle used to travel. The fatigue load history of the frame was obtained from the simulation. Secondly, the amplitude-frequency characteristic of the fatigue load was analyzed. The frequency of the fatigue load mainly focused on 0~20HZ from the analysis. Thirdly, the modal of frame was analyzed. As the frequency of the fatigue load was less than the natural frequency of the frame, the quasi-static method was selected to calculate the stress history of the frame. Next, the fatigue life of the frame was analyzed based on S-N curve. The result showed that the fatigue life of the frame was 69,000 kilometers, which cannot meet the design requirement. Finally, the frame of the electric vehicle was optimized based on the moving least squares response surface model. The objective was to make fatigue life over target and then to minimize mass. The optimization result showed that the mass of the frame increased 11.5%, but the fatigue life of the frame increased from 69,000 kilometers to 304,000 kilometers. The optimized frame had met the design requirement. The optimization results provided reference for the improvement of the frame. The prototype was being trial-produced.