Background: Around the world, policies and interventions are used to encourage clinicians to reduce low-value care. In order to facilitate this, we need a better understanding of the factors that lead to low-value care. We aimed to identify the key factors affecting low-value care on a national level. In addition, we highlight differences and similarities in three countries. Methods: We performed 18 semi-structured interviews with experts on low-value care from three countries that are actively reducing low-value care: the United States, Canada, and the Netherlands. We interviewed 5 experts from Canada, 6 from the United States, and 7 from the Netherlands. Eight were organizational leaders or policy-makers, 6 as low-value care researchers or project leaders, and 4 were both. The transcribed interviews were analyzed using inductive thematic analysis. Results: The key factors that promote low-value care are the payment system, the pharmaceutical and medical device industry, fear of malpractice litigation, biased evidence and knowledge, medical education, and a ‘more is better’ culture. These factors are seen as the most important in the United States, Canada and the Netherlands, although there are several differences between these countries in their payment structure, and industry and malpractice policy. Conclusion: Policy-makers and researchers that aim to reduce low-value care have experienced that clinicians face a mix of interdependent factors regarding the healthcare system and culture that lead them to provide low-value care. Better awareness and understanding of these factors can help policy-makers to facilitate clinicians and medical centers to deliver high-value care.