Clinical practice guidelines (CPG) are widely used tools to enhance quality in healthcare by spreading new knowledge and translating evidence into practice. The first generation of CPGs was developed with the characteristic of evidence based goals. The number of CPGs has increased rapidly. But despite efforts to improve development of CPGs, gaps between research and clinical practice are still apparent. In Sweden, the National Board of Health and Welfare (NBHW) is responsible for national CPGs. Their guideline development model represents second generation CPGs, and balances scientific evidence, financial costs and ethical considerations with the benefit of an evidence based method when prioritizing and formulating recommendations. NBHW recently developed CPGs for prevention that focus on tobacco, alcohol, physical activity and eating habits. The purpose of this study is to investigate and evaluate the process of developing CPGs that address prevention, with a specific focus on how to address challenges related to CPG development, quality and implementation.A mixed methods approach based on archival data, observations, interviews and questionnaires was used.Difficulties related to quality and ambiguity of evidence and recommendations are addressed in the NBHW guideline development model through a systematic CPG development process. The Swedish National Guidelines for Methods of Preventing Disease was the case study. Some difficulties adhering to the NBHW model were found. Quality assessment of these CPGs suggests additional efforts are needed in the areas of development within domains of stakeholder involvement and applicability. First generation CPGs were produced by professionals and mainly confined to summaries of biomedical evidence. Second generation CPGs are characterized by efforts to balance multiple interests (e.g., financial, scientific, ethical) and involve multiple stakeholders (e.g., professions, healthcare providers, patients). There is potential for a third generation CPGs that synthesize the previous generations. They need to be based on the premise that initiating authorities and interacting associations share ownership and cooperate in CPG development, i.e., are active participating stakeholders. Different parties contribute complementary resources in the implementation and clinical use of CPGs.