Objective This paper presents the results of a realist evaluation of a knowledge translation (KT) intervention implemented in the field of health promotion and disease prevention at the local level in France. Design Realist evaluation study. Setting The target population comprised decision-makers and field professionals working in prevention and public health services operating in regions of France (ie, ARS (Agence Régionale de Santé: regional health agency), IREPS (Instance Régionale d'Education et de Promotion de la Santé pour tous: regional organisation for health promotion and education) and their partners). Participants This evaluation was based on data collected from 2 seminars, 82 interviews, 18 observations and 4 focus groups over 18 months. Intervention The TC-REG intervention aimed to increase the use of evidence in cancer prevention, health promotion and disease prevention across four geographical regions in France. The intervention combined various activities: Supporting access to and adaptation of usable evidence, strengthening professionals’ skills in analysing, adopting and using policy briefs, and facilitating the use of evidence in organisations and processes. Results The collected data was used to define favourable/ unfavourable contexts for the use of scientific data and mechanisms to be activated to encourage the use of scientific knowledge. From these raw results eight final refined middle-range theories were defined. Organised around the mechanisms to be activated, these middle-range theories illustrate how to activate knowledge and under what conditions. These analyses provided a basis for the production of seven operational and contextualised recommendations to develop KT to inform regional policymaking regarding health promotion and disease prevention. Conclusion The results obtained from the analyses led us to formulate two perspectives of an operational nature for the benefit of those involved in prevention and health promotion.