High-reliability organizations (eg, the aviation industry) have developed methods for achieving safety despite hazardous conditions. This study describes the development of a framework to achieve high reliability in the intensive care unit (ICU) context and discusses its application to the problem of preventing catheter-related bloodstream infections. The framework is based on a previously published method for evaluating safety interventions; the key elements include selecting measurable outcomes, applying evidence-based interventions, ensuring the intervention reaches all patients, and improving the overall culture of safety. The investigators applied this approach in ICUs in Michigan and achieved significant reductions in the incidence of catheter-related bloodstream infections.