This article explores issues of concern to payers evaluating the hypothetical comparative effectiveness case study of two fictitious migraine treatments in this month’s Health Affairs. The case study presents the seemingly paradoxical situation in which randomized controlled trials produce one result, and real-world observational comparative effectiveness research produces another. For the payer making coverage decisions, this scenario raises three major themes related to interpretation and communication. First, there is a need for a well-considered set of criteria that weigh evidence across comparative effectiveness studies to determine whether enough evidence exists to communicate or enact new health care policies. Second, emphasis should be placed on studies that are published or presented in peer-reviewed settings. Third, access to raw comparative effectiveness research data would enable payers to more deeply explore research interests relevant to their particular constituencies. Payers’ involvement in comparative effectiveness research should be encouraged, not discouraged, to advance our understanding of what works best and for whom.