BACKGROUND: Patient, caregiver, and other stakeholder priorities have not been robustly incorporated into directing hospital-based research and improvement efforts. OBJECTIVE: To systematically engage stakeholders to identify important questions of adult hospitalized patients and to create a prioritized research agenda for improving the care of adult hospitalized patients. DESIGN: A collaborative approach to stakeholder engagement and research question prioritization. SETTING & PARTICIPANTS: Researchers and patients from eight academic and community medical centers partnered with 39 patient, caregiver, professional, research, and medical organizations. METHODS: We applied established standards for formulating research questions and stakeholder engagement. This included: a multi-pronged, inclusive patient and stakeholder engagement strategy; surveys of patients and stakeholder organizations to identify important questions; content analysis of submitted questions; and a 2-day in-person meeting with stakeholder organization representatives and patient partners to prioritize and rank submitted questions. RESULTS: A total of 499 respondents including patients, caregivers, healthcare providers, and researchers from 39 organizations submitted 782 research questions. These questions were categorized into 70 distinct topics-52 that were health system related and 18 disease specific. From these categories, we identified 36 common questions; the final 11 questions were identified, prioritized and ranked during an in-person priority-setting meeting. Questions considered highest priority related to ensuring shared treatment and goals of care decision making and improving hospital discharge handoff to other care facilities and providers. CONCLUSION: We identified 11 prioritized research questions that should galvanize funders, researchers, and patient advocates to address and improve the care of hospitalized adult patients.