OBJECTIVES: To prioritize comparative effectiveness research (CER) questions to improve home dialysis practice using a multicriteria decision analysis (MCDA) framework. METHODS: Candidate CER questions (n=13) were generated and refined in PICO format by an international network of nephrologists (n=28) using a nominal group process. The EVIDEM framework was adapted to include 11 criteria to assess the value of these research questions to improve practice from a holistic standpoint, including the impact, context and outcomes of the CER question, feasibility of study, economics and implementation of study findings. Quality of evidence to be generated was also included as a criterion, with consideration of 13 subcriteria outlining the risk of bias and precision. First, participants were asked to weight each criterion independently of the research questions. Second, for each research question, participants assigned a score for each criterion. Average overall values of CER questions were obtained by combining weights and scores using a linear model. RESULTS: Participants assigned highest importance to the following criteria: Impact on patient survival and other major clinical outcomes, Unmet needs, and Feasibility of the CER question. Value of CER questions varied between 48% and 73% of maximum value on the MCDA scale. Highest value estimates (> 70%) were obtained for research questions exploring the association between vascular access or dialysis selection process and mortality/morbidity. Ranking had excellent face validity for all criteria. Results of this ranking process were used to prioritize research planning for the international network of nephrologists. CONCLUSIONS: Holistic MCDA provides a useful tool for comparative effectiveness research to ensure prioritization of CER questions with highest benefits for improving clinical practice, as illustrated by this application for home dialysis.