Antithrombotic and antiplatelet agents are essential for the management of patients with acute coronary syndromes (ACSs). These pharmacologic agents have the potential for increased risk of bleeding. It is not clear if the increased uptake of these therapies has resulted in a clinically evident increase in bleeding complications over time. In this study, we included 3,193 consecutive patients who were admitted to the University of Michigan with an ACS (unstable angina or myocardial infarction) between January 1999 and December 2004. These patients were analyzed for temporal trends in antithrombotic and antiplatelet agent use, thrombolytic therapy, cardiac catheterizations, percutaneous coronary interventions, and major bleeding complications (including gastrointestinal, vascular access, and intracranial hemorrhage). We found a decreasing temporal trend in the incidence of major in-hospital bleeding complications (p <0.001) despite an increasing use of ticlopidine/clopidogrel (p <0.0001), unfractionated heparin (p <0.01), glycoprotein IIb/IIIa inhibitors (p <0.0001), and percutaneous coronary intervention (p <0.0001) in the management of patients with ACSs. In conclusion, major bleeding remains a significant complication of ACS management but has decreased significantly over time. We believe that this decreasing bleeding trend may be because of better identification of higher risk patients, attention to correct dosing, appropriate monitoring, and incorporation of various periprocedural strategies in routine clinical practice.