Osteoarthritis is a leading cause of disability in the United States. This article describes a prioritized research agenda about osteoarthritis management developed for the Patient-Centered Outcomes Research Institute. Evidence gaps were identified by reviewing existing literature and engaging diverse stakeholders to expand and refine gaps. Stakeholders ranked evidence gaps by importance from their perspectives.Prioritized evidence gaps included the need to determine or evaluate key patient-centered outcomes; optimal duration, intensity, and frequency of nonsurgical interventions; whether the comparative effectiveness of nonsurgical interventions varies by socioeconomic factors; when and how to transition from nonsurgical to surgical interventions; effective ways to engage patients in self-management and promote long-term behavior change; standardized screening tools that improve early diagnosis; biomechanical strategies that improve symptoms; mechanisms for promoting and delivering coordinated, longitudinal care; and comparative effectiveness of nonsurgical therapies. Searches of PubMed and ClinicalTrials.gov showed many recent and ongoing studies addressing comparative effectiveness of nonsurgical interventions; relatively few of these evaluated treatments across categories (for example, drug therapy vs. weight management) or combined categories of treatment. Few studies addressed other high-priority evidence gaps.