In randomized clinical trials, low-molecular-weight heparin enoxaparin has been shown to decrease ischemic complications in patients with acute coronary syndromes (ACSs) without ST elevations who are treated conservatively. Enoxaparin has been shown to be equally effective as unfractionated heparin in high-risk patients with an early invasive approach. Little is known about the use and efficacy of enoxaparin in unselected patients with non–ST-elevation ACSs in clinical practice. In a retrospective analysis of the prospective ACOS registry, we compared the outcome of patients who were >60 years of age with non–ST-elevation myocardial infarction or unstable angina with ST-segment changes who were treated with enoxaparin or unfractionated heparin. In total, 4,806 patients (55%) with non–ST-elevation ACS fulfilled our inclusion criteria for this analysis; 1,178 (25%) were treated with enoxaparin and 3,628 (75%) with unfractionated heparin. There were no differences between groups in baseline characteristics. We observed a significant decrease in the combined end point of death or nonfatal reinfarction with enoxaparin in the entire study group (odds ratio 0.51, 95% confidence interval 0.37 to 0.70) and in subgroups treated with early percutaneous coronary intervention (n = 1,333, odds ratio 0.36, 95% confidence interval 0.17 to 0.80), coronary artery bypass grafting during the index hospitalization (n = 270, odds ratio 0.31, 95% confidence interval 0.04 to 2.42), or conservatively (n = 3,203, odds ratio 0.57, 95% confidence interval 0.40 to 0.81). There was no significant increase in severe bleeding complications with enoxaparin (5.2% vs 4.5%). In conclusion, in clinical practice, in unselected high-risk patients with non–ST-elevation ACSs who are treated conservatively or with early percutaneous coronary intervention, early treatment with enoxaparin is associated with a significant decrease in the combined end point of in-hospital death and reinfarction, without a significant increase in severe bleeding complications.