Background Healthcare organizations seeking to promote a safety culture depend on engaged clinicians. Academic medical centers include a community of physicians-in-training; however, medical residents and fellows are historically less engaged in patient safety (PS) than are other clinicians. Increased attention has been focused on integrating PS into graduate medical education. Nonetheless, developing curricula that result in real-world system changes is difficult. Objective To develop an interactive PS curriculum for internal medicine (IM) residents that analyzes real-word PS problems. Methods A multidisciplinary group developed a five-session, case-based PS curriculum for IM residents in the context of a 3-year, longitudinal quality-improvement, PS, and high-value-care curriculum. The curriculum was facilitated by a PS analyst and incorporated mock root cause analysis (RCA) based on actual resident-reported PS events. Each mock RCA developed an action plan, and outcomes were tracked. Pre- and postcurriculum assessments with participating residents were conducted to evaluate the curriculum. Results Twenty-eight IM residents completed the curriculum during four iterations from 2017 to 2020. The curriculum identified multiple potential PS risks, led to tangible changes in clinical processes, and enhanced resident confidence in improving systems of care. Conclusions We describe an active-learning PS curriculum for IM residents that addressed actual resident-reported PS problems. Through RCA, action items were identified and meaningful system changes were made. Leveraging the expertise of local PS experts in the design and delivery of PS curricula may improve the translation of learner recommendations into real system changes and cultivate a positive PS culture.