BackgroundAction to address the structural determinants of health inequalities is prioritized in high-level initiatives such as the United Nations Sustainable Development Goals and many national health strategies. Yet, the focus of much local policy and practice is on behaviour change. Research shows that whilst lifestyle approaches can improve population health, at best they fail to reduce health inequalities because they fail to address upstream structural determinants of behaviour and health outcomes. In health research, most efforts have been directed at three streams of work: understanding causal pathways; evaluating the equity impact of national policy; and developing and evaluating lifestyle/behavioural approaches to health improvement. As a result, there is a dearth of research on effective interventions to reduce health inequalities that can be developed and implemented at a local level.ObjectiveTo describe an initiative that aimed to mainstream a focus on health equity in a large-scale research collaboration in the United Kingdom and to assess the impact on organizational culture, research processes and individual research practice.MethodsThe study used multiple qualitative methods including semi-structured interviews, focus groups and workshops (n = 131 respondents including Public Advisers, university, National Health Service (NHS), and local and document review.Resultsutilizing Extended Normalization Process Theory (ENPT) and gender mainstreaming theory, the evaluation illuminated (i) the processes developed by Collaboration for Leadership in Applied Health Research and Care North West Coast to integrate ways of thinking and acting to tackle the upstream social determinants of health inequities (i.e. to mainstream a health equity focus) and (ii) the factors that promoted or frustrated these efforts.ConclusionsFindings highlight the role of contextual factors and processes aimed at developing and implementing a robust strategy for mainstreaming health equity as building blocks for transformative change in applied health research.