BACKGROUND: Blood products frequently are administered to critically ill patients. Considering recent trials and practice variability, a comprehensive review of current evidence was deemed essential to offer pertinent guidance to critical care practitioners. This American College of Chest Physicians (CHEST) guidelines panel examined the literature on RBC transfusions among critically ill patients overall and specific subgroups, including patients with gastrointestinal bleeding, acute coronary syndrome (ACS), cardiac surgery, isolated troponin elevation, and septic shock, to provide evidence-based recommendations. STUDY DESIGN AND METHODS: A panel of experts developed six Population, Intervention, Comparator, and Outcome questions addressing RBC transfusions in critically ill patients and performed a comprehensive evidence review. The panel applied the Grading of Recommendations, Assessment, Development, and Evaluations approach to assess the certainty of evidence and to formulate and grade recommendations. A modified Delphi technique was used to reach consensus on the recommendations. RESULTS: The initial search identified a total of 3,082 studies, and after the initial screening, 38 articles were reviewed. Among them, 23 studies met inclusion criteria, comprising 22 randomized controlled trials and one cohort study. Based on the analysis of these studies, the panel formulated two strong and four conditional recommendations. The overall quality of evidence for recommendations ranged from very low to moderate. CONCLUSIONS: In most critically ill patients, a restrictive strategy was preferable to a permissive approach because it does not increase the risk of death or complications, but does decrease RBC use significantly. Data from critically ill subpopulations also supported a restrictive approach, except in patients with ACS, for whom favoring a restrictive approach could increase adverse outcomes.