Background: 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. Methods: 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. Results: 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. Conclusions: Restrictive transfusion strategies should be applied with caution in high-risk patients undergoing major surgery.