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Blood transfusions are associated with morbidity and mortality. However, restrictive thresholds could harm patients less able to tolerate anemia. Using a context-specific approach (according to patient characteristics and clinical settings), the authors conducted a systematic review to quantify the effects of transfusion strategies.The authors searched MEDLINE, EMBASE, CENTRAL, and grey literature sources to November 2015 for randomized controlled trials comparing restrictive versus liberal transfusion strategies applied more than 24 h in adult surgical or critically ill patients. Data were independently extracted. Risk ratios were calculated for 30-day complications, defined as inadequate oxygen supply (myocardial, cerebral, renal, mesenteric, and peripheral ischemic injury; arrhythmia; and unstable angina), mortality, composite of both, and infections. Statistical combination followed a context-specific approach. Additional analyses explored transfusion protocol heterogeneity and cointerventions effects.Thirty-one trials were regrouped into five context-specific risk strata. In patients undergoing cardiac/vascular procedures, restrictive strategies seemed to increase the risk of events reflecting inadequate oxygen supply (risk ratio [RR], 1.09; 95% CI, 0.97 to 1.22), mortality (RR, 1.39; 95% CI, 0.95 to 2.04), and composite events (RR, 1.12; 95% CI, 1.01 to 1.24—3322, 3245, and 3322 patients, respectively). Similar results were found in elderly orthopedic patients (inadequate oxygen supply: RR, 1.41; 95% CI, 1.03 to 1.92; mortality: RR, 1.09; 95% CI, 0.80 to 1.49; composite outcome: RR, 1.24; 95% CI, 1.00 to 1.54—3465, 3546, and 3749 patients, respectively), but not in critically ill patients. No difference was found for infections, although a protective effect may exist. Risk estimates varied with successful/unsuccessful transfusion protocol implementation.Restrictive transfusion strategies should be applied with caution in high-risk patients undergoing major surgery.