Background: Reducing the overuse of care that is proven to be of low value increases the quality and safety of care. We aimed to identify lessons for reducing low-value care by looking at: (1) The effects of eight de-implementation projects. (2) The barriers and facilitators that emerged. (3) The experiences with the different components of the projects. Methods: We performed a process evaluation of eight multicentre projects aimed at reducing low-value care. We reported the quantitative outcomes of the eight projects on the volume of low-value care and performed a qualitative analysis of the project teams' experiences and evaluations. A total of 40 hospitals and 198 general practitioners participated. Results: Five out of eight projects resulted in a reduction of low-value care, ranging from 11.4% to 61.3%. The remaining three projects showed no effect. Six projects monitored balancing measures and observed no negative consequences of their strategy. The most important barriers were a lack of time, an inability to reassure the patient, a desire to meet the patient's wishes, financial considerations and a discomfort with uncertainty. The most important facilitators were support among clinicians, knowledge of the harms of low-value care and a growing consciousness that more is not always better. Repeated education and feedback for clinicians, patient information material and organisational changes were valued components of the strategy. Conclusions: Successfully reducing low-value care is possible in spite of the powerful barriers that oppose it. The projects managed to recruit many hospitals and general practices, with five of them achieving significant results without measuring negative consequences. Based on our findings, we offer practical recommendations for successfully reducing low-value care.