objective. Healthcare-associated infection (HAI) is costly and causes substantial morbidity.We sought to understand why some hospitals were engaged in HAI prevention activities while others were not. Because preliminary data indicated that hospital leadership played an important role, we sought better to understand which behaviors are exhibited by leaders who are successful at implementing HAI prevention practices in US hospitals. methods. We report phases 2 and 3 of a 3-phase study. In phase 2, 14 purposefully sampled US hospitals were selected from among the 72% of 700 invited hospitals whose lead infection preventionist had completed a quantitative survey on HAI prevention during phase 1. Qualitative data were collected during 38 semistructured phone interviews with key personnel at the 14 hospitals. During phase 3, we conducted 48 interviews during 6 in-person site visits to identify recurrent and unifying themes that characterize behaviors of successful leaders. results. We found that successful leaders (1) cultivated a culture of clinical excellence and effectively communicated it to staff; (2) focused on overcoming barriers and dealt directly with resistant staff or process issues that impeded prevention of HAI; (3) inspired their employees; and (4) thought strategically while acting locally, which involved politicking before crucial committee votes, leveraging personal prestige to move initiatives forward, and forming partnerships across disciplines. Hospital epidemiologists and infection preventionists often played more important leadership roles in their hospitaĺs patient safety activities than did senior executives. conclusions. Leadership plays an important role in infection prevention activities. The behaviors of successful leaders could be adopted by others who seek to prevent HAI.