There is an urgent need for an evidence base to guide care for patients with multiple chronic medical conditions (MCC). Comparative effectiveness research (CER) has been touted as 1 solution to generating such evidence. However, the majority of CER topics and methods are designed to generate evidence applicable to single diseases. Generating evidence to guide the care of MCC populations requires thoughtful, and often alternative, approaches to using the existing armamentarium of CER methods. To initiate a dialog about appropriate methods for CER in MCC populations, we discuss advantages and disadvantages of experimental and quasi-experimental study designs for CER in MCC populations, estimating heterogeneity of treatment effects, developing meaningful outcome measures, and aligning morbidity measurement with relevant outcomes. Through an engaged dialog with clinicians, methodologists, and patients, evidence about strengths and limitations of alternative approaches, recommendations about preferred methods for CER in MCC can be developed to ensure that knowledge gaps are filled by valid evidence.