In 2008, the Massachusetts state legislature mandated an examination of the feasibility of the state's participation in establishing a comparative effectiveness center (CEC) and requested recommendations for the entity's design. “Comparative effectiveness” research involves the direct comparative assessment of the efficacy and cost-effectiveness of health care interventions and strategies. The center's findings would guide purchasing and payment decisions related to medical procedures, devices, drugs, and biologics by public- and private-sector organizations. The state has several options in terms of its approach to comparative effectiveness research. It could establish an interstate CEC that synthesizes existing findings for regional decisionmakers, it could establish an interstate CEC that supports new research, it could join an existing CEC, it could join the Drug Effectiveness Review Project and the Medicare Evidence-Based Decisions Project and also establish a regional center, or it could elect not to establish a CEC at all. An exploration of the options and the types of research that could be sponsored reveals that all of the options are potentially feasible, but the legislature's decision with regard to design must consider the level of prioritization of comparative effectiveness research relative to other approaches to improving health care quality and reducing spending growth.