Accurately predicting the fuel savings that can be achieved with the implementation of various technologies developed for fuel efficiency can be very challenging, particularly when considering combinations of technologies. Differences in the usage of highway vehicles can strongly influence the benefits realized with any given technology, which makes generalizations about fuel savings inappropriate for different vehicle applications. A model has been developed to estimate the potential for reducing fuel consumption when advanced efficiency technologies, or combinations of these technologies, are employed on highway vehicles, particularly medium- and heavy-duty trucks. The approach is based on a tractive energy analysis applied to drive cycles representative of the vehicle usage, and the analysis specifically accounts for individual energy loss factors that characterize the technologies of interest. This tractive energy evaluation is demonstrated by analyzing measured drive cycles from a long-haul trucking fleet and the results of an assessment of the fuel savings potential for combinations of technologies are presented. The results of this research will enable more reliable estimates of the fuel savings benefits that can be realized with particular technologies and technology combinations for individual trucking applications so that decision makers can make informed investment decisions for the implementation of advanced efficiency technologies.