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Leaders of academic medical centers (AMCs) are challenged to ensure consistent high performance in quality and safety across all clinical services. The authors sought to identify organizational factors associated with AMCs that stood out from their peers in a composite scoring system for quality and safety derived from patient-level data.A scoring method using measures of safety, mortality, clinical effectiveness, and equity of care was applied to discharge abstract data from 79 AMCs for 2003–2004. Six institutions (three top and three average performers) were selected for site visits; the performance status of the six institutions was withheld from the site visit team. Through interviews and document review, the team sought to identify factors that were associated with the performance status of the institution.The scoring system discriminated performance among the 79 AMCs in a clinically meaningful way. For example, the transition of a typical 500-bed hospital from average to top levels of performance could result in 150 fewer deaths per year. Abstraction of key findings from the interview notes revealed distinctive themes in the top versus average performers. Common qualities shared by top performers included a shared sense of purpose, a hands-on leadership style, accountability systems for quality and safety, a focus on results, and a culture of collaboration.Distinctive leadership behaviors and organizational practices are associated with measurable differences in patient-level measures of quality and safety.