Red blood cell (RBC) transfusions are common in intensive care unit, trauma, and surgical patients. However, the hematocrit that should be maintained in any particular patient because the risks of further transfusion of RBC outweigh the benefits remains unclear. A systematic review of the literature to determine the association between red blood cell transfusion, and morbidity and mortality in high-risk hospitalized patients. MEDLINE, Embase, Cochrane Register of Controlled Trials, and citation review of relevant primary and review articles. Cohort studies that assessed the independent effect of RBC transfusion on patient outcomes. From 571 articles screened, 45 met inclusion criteria and were included for data extraction. Forty-five studies including 272,596 were identified (the outcomes from one study were reported in four separate publications). The outcome measures were mortality, infections, multiorgan dysfunction syndrome, and acute respiratory distress syndrome. The overall risks vs. benefits of RBC transfusion on patient outcome in each study was classified as (i) risks outweigh benefits, (ii) neutral risk, and (iii) benefits outweigh risks. The odds ratio and 95% confidence interval for each outcome measure was recorded if available. The pooled odds ratios were determined using meta-analytic techniques. Forty-five observational studies with a median of 687 patients/study (range, 63-78,974) were analyzed. In 42 of the 45 studies the risks of RBC transfusion outweighed the benefits; the risk was neutral in two studies with the benefits outweighing the risks in a subgroup of a single study (elderly patients with an acute myocardial infarction and a hematocrit <30%). Seventeen of 18 studies, demonstrated that RBC transfusions were an independent predictor of death; the pooled odds ratio (12 studies) was 1.7 (95% confidence interval, 1.4-1.9). Twenty-two studies examined the association between RBC transfusion and nosocomial infection; in all these studies blood transfusion was an independent risk factor for infection. The pooled odds ratio (nine studies) for developing an infectious complication was 1.8 (95% confidence interval, 1.5-2.2). RBC transfusions similarly increased the risk of developing multi-organ dysfunction syndrome (three studies) and acute respiratory distress syndrome (six studies). The pooled odds ratio for developing acute respiratory distress syndrome was 2.5 (95% confidence interval, 1.6-3.3). Despite the inherent limitations in the analysis of cohort studies, our analysis suggests that in adult, intensive care unit, trauma, and surgical patients, RBC transfusions are associated with increased morbidity and mortality and therefore, current transfusion practices may require reevaluation. The risks and benefits of RBC transfusion should be assessed in every patient before transfusion.