The economic assessment of road safety interventions aims to effectively utilize limited available funds in order to maximize benefits. The study aims to present a methodology for the economic assessment of road safety schemes based on historic crash data as well as road safety inspections of the locations under consideration. Using accident prediction models suitably adjusted and calibrated for Greece and adapted according to data availability, the expected benefits from the implementation of road safety schemes are estimated in terms of fatalities and casualties reduction and translated into monetary terms. Taking also into account construction and maintenance costs of each scheme, the economic rate of return (ERR) is estimated. A pilot implementation of the methodology was performed for the Road Safety Interventions Design Studies of the Road Safety Program of Egnatia Odos for the sub-regions of Viotia and Imathia. The economic rates of return were estimated at 27,1% for Viotia and 18,2% for Imathia, demonstrating the very high cost effectiveness of road safety schemes.