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Introduction: Foundational to a learning health system (LHS) is the presence of a data infrastructure that can support continuous learning and improve patient outcomes. To advance their capacity to drive patient-centered care, health systems are increasingly looking to expand the electronic capture of patient data, such as electronic patient-reported outcome (ePRO) measures. Yet ePROs bring unique considerations around workflow, measurement, and technology that health systems may not be poised to navigate. We report on our effort to develop generalizable learnings that can support the integration of ePROs into clinical practice within an LHS framework. Methods: Guided by action research methodology, we engaged in iterative cycles of planning, acting, observing, and reflecting around ePRO use with two primary goals: (1) mobilize an ePRO community of practice to facilitate knowledge sharing, and (2) establish guidelines for ePRO use in the context of LHS practice. Multiple, emergent data collection activities generated generalizable guidelines that document the tangible best practices for ePRO use in clinical care. We organized guidelines around thematic areas that reflect LHS structures and stakeholders. Results: Three core thematic areas (and 24 guidelines) emerged. The theme of governance reflects the importance of leadership, knowledge management, and facilitating organizational learning around best practice models for ePRO use. The theme of integration considers the intersection of workflow, technology, and human factors for ePROs across areas of care delivery. Lastly, the theme of reporting reflects critical considerations for curating data and information, designing system functions and interactions, and presentation of ePRO data to support the translation of knowledge to action. Conclusions: The guidelines produced from this work highlight the complex, multidisciplinary nature of implementing change within LHS contexts, and the value of action research approaches to enable rapid, iterative learning that leverages the knowledge and experience of communities of practice.