Objectives Soliciting stakeholder input is becoming commonplace in comparative effectiveness research (CER), yet methods for stakeholder engagement in CER are evolving.  Drawing from CMTP and University of Maryland’s experiences across a variety of NIH, PCORI, and industry-funded activities as well as previously published case analyses, we describe a framework for stakeholder engagement in CER that standardizes approaches for generating meaningful evidence. Methods We conducted a literature search to explore engagement practices in biomedical sciences, social sciences, and business which included the gray literature.  The results were combined with investigator experience to develop a process framework and corresponding activities for successful stakeholder engagement.   Results We defined five steps- recruitment, preparation, engagement, dissemination, and evaluation- broadly applicable to stakeholder engagement.  Recruitment should begin with clearly defined expectations for involvement and end with balanced representation of stakeholders that meet the needs of the project and disclose conflicts of interest. Preparing stakeholders for participation in CER requires customized and relevant background materials. Stakeholder engagement by an experienced facilitator should guide iterative engagement procedures by using deliberative methods that ensure a fair, competent and trustworthy process.  Dissemination must document the stakeholders’ input and how this information was incorporated into decision-making or pathways for implementation.  Publications should also acknowledge stakeholder involvement and contributions. Following dissemination, evaluation provides both researchers and stakeholders an opportunity to assess the engagement experience and outcomes, which is necessary for refining practices for future work.   Conclusions CER is transitioning toward an interactive framework of stakeholder engagement that enhances the traditional research paradigm.  This process model provides a standard methodology to guide this transition to stakeholder-based research.  This process is adaptable across multiple CER activities including priority-setting, study design, and methods guidance as well as various therapeutic areas.  Further research is needed to refine, evaluate, and apply this model to ongoing CER activities.