Background: Clinical practice guidelines (CPGs) have become central to efforts to change clinical practice and improve the quality of health care. Despite growing attention for rigorous development methodologies, it remains unclear what contribution CPGs make to quality improvement. Aim: This mixed methods study examines guideline quality in relation to the availability of certain types of evidence and reflects on the implications of CPGs' promise to improve the quality of care practices. Methods: The quality of 62 CPGs was assessed with the Appraisal of Guidelines, Research, and Evaluation (AGREE) instrument. Findings were discussed in 19 followup interviews to examine how different quality aspects were considered during development. Results: The AGREE assessment showed that while some quality criteria were met, CPGs have limited coverage of domains such as stakeholder involvement and applicability, which generally lack a 'strong' evidence base (e.g., randomized controlled trials [RCT]). Qualitative findings uncovered barriers that impede the consolidation of evidence-based guideline development and quality improvement including guideline scoping based on the patient-intervention-comparison-outcome (PICO) question format and a lack of clinical experts involved in evidence appraisal. Developers used workarounds to include quality considerations that lack a strong base of RCT evidence, which often ended up in separate documents or appendices. Conclusion: Findings suggest that CPGs mostly fail to integrate different epistemologies needed to inform the quality improvement of clinical practice. To bring CPGs closer to their promise, guideline scoping should maintain a focus on the most pertinent quality issues that point developers toward the most fitting knowledge for the question at hand, stretching beyond the PICO format. To address questions that lack a strong evidence base, developers actually need to appeal to other sources of knowledge, such