In this study a simplified Willans line approach is used to model the CO2 emissions of a long-haul tractor-semitrailer combination. The results are validated with PEMS measurements and show that high accuracy levels can be achieved, if the vehicle and cycle specific parameters are known. It is shown that the same approach can be used to calculate and predict the savings potential of a reduction measure and that the effectiveness strongly depends on the vehicle weight and the velocity profile. Based on the measured effects of vehicle and system measures from recent studies, the generic approach is used to determine the cumulative effect of a given package of fuel efficiency measures, including: energy carriers, vehicle technologies and operational improvements. The cumulative savings potential is determined for two use cases: a city distribution rigid truck and a long-haul tractor-semitrailer. The results show that large CO2 savings can be achieved when using an integrated approach of vehicle and system measures together. For the city distribution rigid truck, large CO2 reductions are achieved with electric drivetrains in combination with a clean well-to-tank electricity production whereas improved engine efficiency, reduced road load and logistic options are more promising solutions for the long-haul tractor-semitrailer.