OBJECTIVES: Coincident with the increasing focus on comparative effectiveness research (CER), a number of organizations have begun to engage in prioritizing topics for CER.  This paper presents the priority-setting process developed by the Center for Medical Technology Policy (CMTP) and its application to the selection of cardiac technologies. METHODS:  We reviewed criteria and processes used by other organizations.  We then developed a multi-stage process including, 1) horizon scanning; 2) topic nomination; 3) expert solicitation; 4) topic review and selection; 5) criteria application and discussion by a expert workgroup, and 6) final ranking of topics for varied research projects. After internally refining a broad list to the top ten technologies, we convened an expert workgroup charged with ranking these top technologies using prospectively developed criteria.  Experts were provided with a list of criteria and briefs summarizing clinical, economic, and ethical aspects of each technology. RESULTS: Topic nomination produced an initial list of approximately 40 technologies, which were narrowed to the top ten based on suitability for CMTP’s coverage with evidence development (CED) initiatives and guidelines for designing CER studies projects.  The expert working group ranked technologies according to suitability for both CED and the guideline projects. The top 3 technologies that emerged for CED were 1) pharmacogenetic guidance of warfarin dosing; 2) catheter ablation for atrial fibrillation; and 3) percutaneous aortic valve replacement.  For the guidelines, the ranking was 1) C-reactive protein tests; 2) genetic testing for heart disease; and 3) bioabsorbable stents.  CONCLUSIONS: A prospectively developed multi-step process focusing on technologies within a disease area may improve the process of prioritizing technologies for CER, offering more direct guidance to researchers and policy makers. Notably, CMTP is initiating a CED project and the advisory workgroup selected the warfarin dosing topic, indicating the success of the process in choosing a relevant technology.