The nine NIHR CLAHRCs are collaborations between universities and local NHS organizations that seek to improve patient outcomes through the conduct and application of applied health research. The theoretical and practical context within which the CLAHRCs were set up was characterized by a considerable degree of uncertainty, and the CLAHRCs were established as a natural experiment. We adopted a formative and emergent evaluation approach. Drawing on in-depth, multi-method case studies of two CLAHRCs we explored how they pursued their remit by supporting efforts to increase the relevance and use of health research, and building relationships. Both CLAHRCs: strengthened local networks and relationships; built capacity in their local academic and NHS communities to undertake and use research that meets the needs of the service; developed research and implementation methodologies; and added to understanding of the complex relation between research and implementation. There was evidence of impact of CLAHRC projects on health and social care services. Informed by the literature on implementing collaborative research initiatives, knowledge transfer and exchange and cultural change, some key lessons can be drawn. The CLAHRCs pursued a strategy that can be categorized as one of flexible comprehensiveness; i.e. their programmes have been flexible and responsive and they have used a range of approaches that seek to match the diverse aspects of the complex issues they face. Key features include their work on combining a range of knowledge transfer and exchange strategies, their efforts to promote cultural change, and the freedom to experiment, learn and adapt. Although the CLAHRCs do not, by themselves, have the remit or resources to bring about wholesale service improvement in health care, they do have features that would allow them to play a key role in some of the wider initiatives that encourage innovation.