Antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), are frequent sources of hospital-acquired infection (HAI) in the intensive care unit (ICU). Although the incidence of serious infections caused by MRSA has been decreasing, the optimal strategies to prevent spread of these bacteria remain unclear. In this cluster-randomized trial conducted in 18 ICUs, a protocol that involved universal surveillance and barrier precautions (gowns and gloves) for patients colonized with these bacteria was evaluated for effectiveness at preventing colonization and infection with MRSA or VRE. No reduction in colonization or infection was found, in part attributable to the fact that use of barrier precautions was suboptimal. Prior successful efforts to reduce HAI have emphasized the role of safety culture in addition to specific preventive interventions, an approach discussed in-depth in this analysis of the landmark Keystone ICU project.