The purpose of this article is to describe factors contributing to potentially preventable mortality in academic medical centers and the organizational characteristics associated with success in reducing mortality. Sixteen U.S. academic medical centers that wished to improve risk-adjusted inpatient mortality rates requested a consultation that included interviews with physicians, nurses, and hospital leaders; review of medical records; and evaluation of systems and processes of care. The assessments took place on-site; they identified key factors contributing to preventable mortality, and each hospital received specific recommendations. Changes in observed mortality and in the ratio of observed to expected mortality were measured from 2002 to final follow-up in 2007. Evaluations determined each hospital's success factors and key barriers to improvement. The key factors contributing to preventable mortality were delays in responding to deteriorating patients, suboptimal critical care, hospital-acquired infections, postoperative complications, medical errors, and community issues such as the availability of hospice care. Of the 16 hospitals, 12 were able to reduce their mortality index. The five hospitals that had the greatest improvement in mortality were the only hospitals with a broad level of engagement among hospital and physician leaders, including the department chairs. In the hospitals whose performance did not improve, the department chairs were not engaged in the process. The academic medical centers that focused on mortality reduction and had engagement of physicians, especially department chairs, were able to achieve meaningful reductions in hospital mortality. The necessary ingredients for achieving meaningful improvement in clinical outcomes included good data, a sound method for change, and physician leadership.