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Background: Many interventions used in health care lack evidence of effectiveness and may be unnecessary or even cause harm, and should therefore be de-implemented. Lists of such ineffective, low-value practices are common, but these lists have little chance of leading to improvements without sufficient knowledge regarding how de-implementation can be governed and carried out. However, decisions regarding de-implementation are not only a matter of scientific evidence; the puzzle is far more complex with political, economic, and relational interests play a role. This project aims at exploring the governance of de-implementation of low-value practices from the perspectives of national and regional governments and senior management at provider organizations. Methods: Theories of complexity science and organizational alignment are used, and interviews are conducted with stakeholders involved in the governance of low-value practice de-implementation, including national and regional governments (focusing on two contrasting regions in Sweden) and senior management at provider organizations. In addition, an ongoing process for governing de-implementation in accordance with current recommendations is followed over an 18-month period to explore how governance is conducted in practice. A framework for the governance of de-implementation and policy suggestions will be developed to guide de-implementation governance. Discussion: This study contributes to knowledge about the governance of de-implementation of low-value care practices. The study provides rich empirical data from multiple system levels regarding how de-implementation of low-value practices is currently governed. The study also makes a theoretical contribution by applying the theories of complexity and organizational alignment, which may provide generalizable knowledge about the interplay between stakeholders across system levels and how and why certain factors influence the governance of de-implementation. The project employs a solution-oriented perspective by developing a framework for de-implementation of low-value practices and suggesting practical strategies to improve the governance of de-implementation. The framework and strategies can thereafter be evaluated for validity and impact in future studies.