OBJECTIVES: Antiplatelet and antithrombotic therapies have long been the focus of extensive clinical and economic investigations. In many of these studies, the primary endpoint of analysis was the incidence of “major bleeding.” Unfortunately, major bleeding does not have a standard or universal definition. Major cardiovascular studies such as GUSTO, CURE, TIMI and the International Society on Thrombosis and Haemostasis (ISTH) have each established definitions that result in vastly different outcomes. Additionally, none of the common definitions were designed for patients undergoing surgery as part of their care. Analyses that compare outcomes from multiple trials must carefully examine the definitions used. METHODS: We analyzed the effect of applying 6 major bleeding definitions on the incidence and costs of care for acute coronary syndrome (ACS) patients undergoing coronary artery bypass graft surgery (CABG) in their index hospitalization in a previously developed database of ACS patients from 14 health systems across the United States. RESULTS: Our comparison found that application of the different definitions could result in a large variance in the primary outcome of “major bleeding” with equal impact on the comparisons for the cost of care. The incidence of major bleeding varied by as much as 50% as did the cost of treatment. The data review included ACS patients who underwent CABG between January 2005 and December 2006. CONCLUSIONS: Comparing the incidence, impact and costs of treating major bleeding between various clinical trials requires a careful assessment of the definitions used. Development of a single standard definition of “major bleeding” for use in clinical and observational trials is recommended.