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Central line-associated bloodstream infections (CLABSIs) are a common and costly quality problem, and their prevention is a national priority. A decade ago, researchers identified an evidence-based bundle of practices that reduce CLABSIs. Compliance with this bundle remains low in many hospitals.The aim of this study was to assess whether differences in core aspects of work environments—workload, quality of relationships, and prioritization of quality—are associated with variation in maximal CLABSI bundle compliance, that is, compliance 95%–100% of the time in intensive care units (ICUs).A cross-sectional study of hospital medical-surgical ICUs in the United States was done. Data on work environment and bundle compliance were obtained from the Prevention of Nosocomial Infections and Cost-Effectiveness Refined Survey completed in 2011 by infection prevention directors, and data on ICU and hospital characteristics were obtained from the National Healthcare Safety Network. Factor and multilevel regression analyses were conducted.Reasonable workload and prioritization of quality were positively associated with maximal CLABSI bundle compliance. High-quality relationships, although a significant predictor when evaluated apart from workload and prioritization of quality, had no significant effect after accounting for these two factors.Aspects of the staff work environment are associated with maximal CLABSI bundle compliance in ICUs. Our results suggest that hospitals can foster improvement in ensuring maximal CLABSI bundle compliance—a crucial precursor to reducing CLABSI infection rates—by establishing reasonable workloads and prioritizing quality.