Background: Transfer of a process, technology or method from one setting to another is often challenging and clinical practice guideline adaptation is not an exception. The aim of this study was to identify the challenges of clinical practice guideline adaptation in Iran and provide lessons for developing countries.Methods: In this qualitative study, purposeful interviews were conducted with 17 participants from guideline adaptation groups in research centers , knowledge management and health department of Tehran University of Medical Sciences and experts in ministry of health. Data was analyzed using qualitative content analysis. Results: The identified challenges were classified into two basic and operational categories. Basic challenges include believing in need to guideline adaptation, position of adaptation in evaluation and reward systems, access to financial resources and supervision of adaptation process. Also operational challenges were adaptation methodology, forming adaptation team, consensus on interdisciplinary issues, changing programs and priorities and external barriers in the work progress path. Conclusions: Having a comprehensive list of problems will help health system managers and policymakers to control the quality of clinical practice guidelines and could eventually lead to corrective actions. From the most important proposed interventions for removing the current obstacles and problems are holding new training courses and programs for these guides users at different headquarters’ and environmental levels, establishing an appropriate motivating system, designing an integrated system with a focus on organizing related stewardship affairs including planning, policy making and supervision at the treatment deputy of ministry of health and universities levels.