Guideline developers are increasingly dealing with more difficult decisions concerning whether to recommend complex interventions in complex and highly variable health systems. There is greater recognition that both quantitative and qualitative evidence can be combined in a mixed-method synthesis and that this can be helpful in understanding how complexity impacts on interventions in specific contexts. This paper aims to clarify the different purposes, review designs, questions, synthesis methods and opportunities to combine quantitative and qualitative evidence to explore the complexity of complex interventions and health systems. Three case studies of guidelines developed by WHO, which incorporated quantitative and qualitative evidence, are used to illustrate possible uses of mixed-method reviews and evidence. Additional examples of methods that can be used or may have potential for use in a guideline process are outlined. Consideration is given to the opportunities for potential integration of quantitative and qualitative evidence at different stages of the review and guideline process. Encouragement is given to guideline commissioners and developers and review authors to consider including quantitative and qualitative evidence. Recommendations are made concerning the future development of methods to better address questions in systematic reviews and guidelines that adopt a complexity perspective