Abstract: In recent years, the high-speed railway Bridge in China is rapidly developing and is toward to the central and western regions with strong earthquakes. Thus, it is of a great significance to study on the train running safety of the High-Speed Railway Bridge. Based on Simpack (multi-body dynamics software) and OpenSees (finite element software), a co-simulation system of vehicle-track-bridge (SOTTB) is developed, and the SOTTB exerts both advantage. Then, the accuracy and feasibility of the Vehicle-track-bridge Cosimulation system method by Simpack and OpenSees is verified by the time-history analysis of a simply supported bridge. Based on the numerical model of a high-speed train-track-bridge system by SOTTB, the safety of train operation under the excitation of transverse earthquakes and track irregularity is studied. The space vibration model of the German high-speed train (ICE) is adapted, and the wheel-rail force is calculated by Hertzian nonlinear elastic contact theory and simplified Kaller's creep theory. The results indicate that there is an obvious trend of increase upon vehicle indicators and body acceleration, with the increase of earthquake intensity and operating speed. The earthquake intensity has a significant effect upon the lateral wheel-rail force and the lateral acceleration of vehicle. The lateral wheel-rail force and the lateral acceleration of vehicle increase significantly with the increase of earthquake intensity. The load reduction rate and vertical acceleration of train are less affected by the seismic intensity, and the speed of train is the main factor that affects the wheel-load reduction rate.