Despite substantial improvement in recent years in hospital performance in many quality measures for acute myocardial infarction (AMI), national performance lags in a key publicly reported quality indicator for AMI--door-to-balloon time, the period from patient (with ST-segment elevation myocardial infarction or STEMI) arrival to provision of percutaneous coronary intervention or balloon angioplasty. Previous research has elucidated distinguishing features of hospitals that routinely achieved recommended door-to-balloon times for patients with STEMI. However, what has not been fully explored is how top-performing hospitals handle setbacks during the improvement process. In this study, we used qualitative methods to characterize the range of setbacks in door-to-balloon improvement efforts and the strategies used to address these barriers among hospitals that were ultimately successful in reducing door-to-balloon time to meet clinical guidelines. Setbacks included (1) failure to anticipate and address implications of initial changes in door-to-balloon processes for the system as a whole; (2) tension between and within departments and disciplines, which needed to gain consensus about how to reduce door-to-balloon time; and (3) waning attention to door-to-balloon performance as a top priority after the perceived goal of reducing treatment times had been reached. Our findings demonstrate key aspects of technical capacity, organizational culture, and environmental conditions that were factors in maintaining improvement efforts despite setbacks and hence may be critical to sustaining top performance. Understanding how top-performing hospitals recognize and respond to setbacks can help senior management promote organizational resiliency, leading to an environment in which learning, growth, and quality improvement can be sustained.