Major bleeding has been associated with an increased risk of ischemic events and death in patients with acute coronary syndromes. We examined the relationship between bleeding and outcome in 1,389 consecutive patients with ST-elevation myocardial infarction (STEMI) presenting to a tertiary center between May 1, 2003 and July 10, 2007. We recorded bleeding, length of stay and death during the first 30 days after hospitalization. Major bleeding occurred in 10.9% (152/1389, 95% confidence interval [CI] 9.3-12.6%). In hospital mortality was significantly higher in patients with major bleeding compared to those without major bleeding (19.7 vs. 8.2%, odds ratio [OR] 2.8, 95% CI 1.8-4.3) and was evident in the subgroups of patients with a low TIMI STEMI risk score (7.9 vs. 1.8%, OR 4.6, 95% CI 1.2-17.0) and medium risk score (11.7 vs. 6.3%, OR 2.0, 95% CI 0.6-6.2) but not those with a high TIMI STEMI risk score (28.8 vs. 26.1%, OR 1.2, 95% CI 0.7-2.0) (P for interaction = 0.024). Our data indicate that serious bleeding is common in patients with STEMI treated with thrombolysis or PCI and is a powerful predictor of death, particularly in patients with a low TIMI risk score. Therapies that maintain efficacy while reducing bleeding and that reduce the risk of death in patients who develop bleeding are needed.