The economic appraisal of transport projects is a vital component of decision making in road infrastructure investments. The economic appraisal of road safety schemes however is not common practice; aspects such as the estimation of the expected reduction in crashes and casualties, as well as the monetary valuation of human life and injury must be addressed in order to produce reliable results. The paper presents a methodology for the economic appraisal of road safety schemes on two-lane rural road sections and intersections in Greece. The methodology combines two approaches in road safety, namely reactive and proactive engineering in a holistic method to estimate the benefits of road safety schemes. According to the reactive approach, Accident Prediction Models, based on the AASHTO Highway Safety Manual are used, calibrated for Greece using local crash and traffic data, to estimate the expected crash, fatalities and casualties reduction if the suggested interventions are fully implemented. Road Safety Inspections (proactive road safety engineering) are also used to identify road safety deficiencies and assist in addressing them even before accidents occur. Results of both approaches are combined and the expected road safety benefits are translated into monetary terms; finally, considering relevant costs, the project’s economic rate of return is estimated. A pilot implementation of the methodology was performed for the economic appraisal of suggested low cost interventions in two sub-regions of Greece. The economic assessment concluded that a very high economic rate of return can be expected in both sub-regions.