Antithrombotic therapy reduces the risk of recurrent ischemic events in patients with unstable angina. The primary aim of the ESSENCE trial is to evaluate the efficacy of enoxaparin (low molecular weight heparin) versus unfractionated heparin, plus aspirin, in patients with rest angina or non-Q-wave infarction. This is a randomized, double-blind, placebo-controlled study of 3180 patients comparing enoxaparin, 1 mg/kg sc bid, with unfractionated heparin via continuous iv infusion to maintain the aPTT at 2 x control. Patients within 24 hours of the onset of acute myocardial ischemia without ST elevation are eligible, and trial therapy is administered for a minimum of 48 hours to a maximum of 8 days. Primary endpoints analyzed are death, myocardial infarction (MI), or recurrent angina at 14 days. Currently 3019 patients have been randomized in 10 countries. The mean age is 64 years, 33% are female, and 46% have had a prior MI. The overall event rates at 14 days are 1.7% mortality, 5.9% subsequent MI, and 17% recurrent angina. The composite triple endpoint rate is 23.6%. Recruitment should be complete by June 1996. The methods and design of the study are presented in this article.