In order to study the effect of wheel harmonic wear on train operation safety, the simulation model of train-track-subgrade coupling system which considered rail and track plate vibration was established. According to the harmonic order of the first-order, sixthorder and eleventh-order in the wave depth of 0.1 mm and 0.3 mm, the wheel-load reduction rate, derailment coefficient and wheel/ rail lateral force were researched and analyzed based on relevant railway standard. The results showed that the maximum derailment coefficient was in the range of safety limit under the different forms of the harmonic wear wheel, and the derailment phenomenon would not occur; But the maximum wheel-load reduction rate exceeded the safety limit of 0.8, and the maximum wheel/rail lateral force was close to the national standard limit value, which had security risks. This study was helpful to evaluate the influence of wheel harmonic wear on the safety of high-speed vehicle, and provided the theoretical basis for vehicle operation safety.