The implementation of Trajectory-Based Operations, invented by the Single European Sky Air Traffic Management Research program SESAR, enables airlines to fly along optimized waypoint-less trajectories and accordingly to significantly increase the sustainability of the air transport system in a business with increasing environmental awareness. However, unsteady weather conditions and uncertain weather forecasts might induce the necessity to re-optimize the trajectory during the flight. By considering a re-optimization of the trajectory during the flight they further support air traffic control towards achieving precise air traffic flow management and, in consequence, an increase in airspace and airport capacity. However, the re-optimization leads to an increase in the operator and controller’s task loads which must be balanced with the benefit of the re-optimization. From this follows that operators need a decision support under which circumstances and how often a trajectory re-optimization should be carried out. Local numerical weather service providers issue hourly weather forecasts for the coming hour. Such weather data sets covering three months were used to re-optimize a daily A320 flight from Seattle to New York every hour and to calculate the effects of this re-optimization on fuel consumption and deviation from the filed path. Therefore, a simulation-based trajectory optimization tool was used. Fuel savings between 0.5% and 7% per flight were achieved despite minor differences in wind speed between two consecutive weather forecasts in the order of 0.5 m s−1. The calculated lateral deviations from the filed path within 1 nautical mile were always very small. Thus, the method could be easily implemented in current flight operations. The developed performance indicators could help operators to evaluate the re-optimization and to initiate its activation as a new flight plan accordingly.