BACKGROUND: Prior retrospective studies have identified a relationship between bleeding after cardiac surgery and subsequent mortality. Whether this is attributable to bleeding, anemia, or transfusions is undetermined. METHODS: ACUITY was an international prospective trial of patients with acute coronary syndromes. Coronary artery bypass grafting (CABG) before hospital discharge was performed in 1,491 patients. Major bleeding was adjudicated as CABG- or non-CABG related. The relationship between CABG-related bleeding and 1-year mortality was determined using a time-updated covariate-adjusted Cox model. RESULTS: Coronary artery bypass grafting-related major bleeding after surgery occurred in 789 patients (52.9%); allogeneic blood product transfusions were administered in 612 patients (41.0%), including red blood cell (RBC) transfusions in 570 (38.2%, range 1-53 U), platelet transfusions in 180 (12.1%), and fresh-frozen plasma in 195 (13.1%). One-year mortality occurred in 95 patients (6.4%). Red blood cell transfusion (but not transfusion of platelets or fresh-frozen plasma, CABG-related major bleeding per se, or nadir hemoglobin) was an independent predictor of 1-year mortality, but only after transfusion of ≥4 U (adjusted hazard ratio for death after transfusion of 1-3, 4-6, and ≥7 RBC units = 0.74, 2.01, and 5.22, respectively). Of the 95 deaths after CABG, 23 (24.2%) were attributable to CABG-related RBC transfusions. CONCLUSIONS: In patients with acute coronary syndromes, RBC transfusion of ≥4 U after CABG is strongly associated with subsequent mortality. Future strategies should focus on reducing major hemorrhagic complications and RBC transfusions after CABG.