- Background The broad utilization of revascularization and antithrombotic therapy in patients with acute coronary syndrome (ACS) is associated with a substantial risk of bleeding primarily related to arterial punctures, which can lead to worse outcome. Aim To define the characteristics and outcome of patients who develop upper gastrointestinal bleeding (UGIB) in the setting of ACS. Methods We identified all patients admitted to the coronary care unit between 10/96 and 11/07 with ACS who developed UGIB. For each case 3 control cases were matched. Multiple baseline characteristics, as well as antithrombotic agents, revascularization strategy and endoscopy reports were assessed. Mortality at 30-day was the primary endpoint of the analysis. Results Of 7240 ACS patients, 64 (0.9%) developed UGIB. There were no significant differences between groups in the prevalence of diabetes and other risk factors, revascularization strategy, or the use of proton pump inhibitors. Patients with UGIB suffered more from renal impairment and left ventricular dysfunction and were more frequently treated with thienopyridines (89% vs. 68%, p = 0.002) and glycoprotein IIb/IIIa inhibitors (39% vs. 24%, p = 0.03). The combination of unfractionated heparin (UFH) with glycoprotein IIb/IIIa inhibitors was strongly associated with UGIB (OR: 2.87, 95% CI 1.66–4.97). Patients who developed UGIB had a substantially higher 30-day mortality rate (33% vs. 5%, p < 0.001). Conclusions UGIB in patients with ACS is associated with a markedly increased mortality. Previous peptic disease and the use of combined anti-platelet therapy, especially in conjunction with heparin, are strong risk factors for this serious complication.