Background: Much research does not address the practical needs of stakeholders responsible for introducing health care delivery interventions into organizations working to achieve better outcomes. In this article, we present an approach to using the Consolidated Framework for Implementation Research (CFIR) to guide systematic research that supports rapid-cycle evaluation of the implementation of health care delivery interventions and produces actionable evaluation findings intended to improve implementation in a timely manner. Methods: To present our approach, we describe a formative cross-case qualitative investigation of 21 primary care practices participating in the Comprehensive Primary Care (CPC) initiative, a multi-payer supported primary care practice transformation intervention led by the Centers for Medicare and Medicaid Services. Qualitative data include observational field notes and semi-structured interviews with primary care practice leadership, clinicians, and administrative and medical support staff. We use intervention-specific codes, and CFIR constructs to reduce and organize the data to support cross-case analysis of patterns of barriers and facilitators relating to different CPC components. Results: Using the CFIR to guide data collection, coding, analysis, and reporting of findings supported a systematic, comprehensive, and timely understanding of barriers and facilitators to practice transformation. Our approach to using the CFIR produced actionable findings for improving implementation effectiveness during this initiative and for identifying improvements to implementation strategies for future practice transformation efforts. Conclusions: The CFIR is a useful tool for guiding rapid-cycle evaluation of the implementation of practice transformation initiatives. Using the approach described here, we systematically identified where adjustments and refinements to the intervention could be made in the second year of the 4-year intervention. We think the approach we describe has broad application and encourage others to use the CFIR, along with intervention-specific codes, to guide the efficient and rigorous analysis of rich qualitative data.