Background: Comparative effectiveness research and patient-centered outcomes research (CER/PCOR) can play a critical role in improving both processes and outcomes of healthcare in the United States. For CER/PCOR to meet this potential, the research will need to address topics of high relevance and to study interventions that can be implemented in real-world settings. These concerns are especially pressing for high-risk populations such as those served by Medicaid. Identifying the best set of priority topics for CER will require a combined approach that obtains input from a wide variety of perspectives, but refines that input with insight into the research areas most likely to yield productive and actionable information.