Background: The objective of this presentation is to provide an overview of the conceptual, theoretical and methodological challenges of a research project in health promotion that uses the Yin’s multiple case study methodology with the Pawson and Tilley’s realist approach. Currently, even if this type of study begins to be carried out and published in this research field, the subsequent challenges are not often discussed by its users. Method: We illustrate these challenges with a research project in which we are involved in. The aim of the project is to understand and explain how designers of population health intervention research (PHIR) produce knowledge on health inequalities and foster its use in public action for reducing health inequalities at the local level in France. In the project, the stages of the Yin’s multiple case study methodology were combined to the conceptual and theoretical framework of the realist approach. Two cases of population health intervention research are eligible. Firstly, for each case, the initial ‘program theory’ of the integrated knowledge translation strategies was constructed and refined with the designers of each PHIR. Secondly, a cross case analysis allowed to build the initial middle-range theory of all strategies. This theory will be refined during a seminar with the designers and others involving in PHIR implemented during the research project at the local level in France. Each theory is translated into Context-Mechanism-Outcome configuration. Results: Various conceptual, theoretical and methodological challenges were highlighted for carrying out a multiple case study with the realist approach. 1) Conceptual challenges: • The key concepts of the realist approach (i.e. mechanism, context, strategy, outcome) need a significant time of appropriation and their application is more or less complex according to the nature of the intervention; • The different contextual levels of the intervention need to be clarified and linked together (e.g. research and/or intervention contexts of a PHIR), taking into account the space and temporality of the intervention; 2) Theoretical challenges: • The comprehension of the logic of intervention by researchers involves an active participation of stakeholders during the development of theories; • The follow-up throughout the research project is essential to take into account the evolution of the logic of intervention; • The choice to develop CMO configurations on the basis of either a specific mechanism or a specific outcome is crucial during a multiple case study to initiate the development of a program theory or a middle-range theory. 3) Methodological challenges: • The development and analysis of theories (i.e. CMO configurations) require a substantial time and a technical and logistical preparation; • The development of suitable and easy to use tools that facilitate the abductive process to test and refine theories with stakeholders. Conclusion: This presentation will stimulate a discussion on the operationalization of a multiple case study with the realist approach, and more broadly, on the practices of the realist approach in research.