The growing burden of road traffic injuries, which kill over 1.2 million people yearly, falls mostly on low- and middle-income countries (LMICs). Despite this, evidence generation on the effectiveness of road safety interventions in LMIC settings remains scarce. This paper explores a scientific approach for evaluating road safety programmes in LMICs and introduces such a road safety multi-country initiative, the Road Safety in 10 Countries Project (RS-10). By building on existing evaluation frameworks, we develop a scientific approach for evaluating large-scale road safety programmes in LMIC settings. This also draws on '13 lessons' of large-scale programme evaluation: defining the evaluation scope; selecting study sites; maintaining objectivity; developing an impact model; utilising multiple data sources; using multiple analytic techniques; maximising external validity; ensuring an appropriate time frame; the importance of flexibility and a stepwise approach; continuous monitoring; providing feedback to implementers, policy-makers; promoting the uptake of evaluation results; and understanding evaluation costs. The use of relatively new approaches for evaluation of real-world programmes allows for the production of relevant knowledge. The RS-10 project affords an important opportunity to scientifically test these approaches for a real-world, large-scale road safety evaluation and generate new knowledge for the field of road safety.