The importance of aldosterone in the pathophysiology of chronic heart failure (HF) has been established in previous studies [1–4] and is emphasized by the findings of the RALES trial [5]. In this study, aldosterone blockade with spironolactone resulted in a 30% reduction in total mortality and a 35% reduction in hospitalizations for HF in patients with pre-existing chronic severe HF. Patients in the RALES trial also received standard therapy including an ACE inhibitor (if tolerated), a loop diuretic, and digoxin. While aldosterone receptor blockade has been proven beneficial in severe chronic HF due to systolic left ventricular (LV) dysfunction, its effects in patients with acute myocardial infarction (AMI) complicated by HF due to systolic left ventricular dysfunction are unknown. The pathophysiology of HF complicating AMI is complex. Factors such as the acute release of catecholamines, activation of the renin angiotensin aldosterone system, degree of ventricular remodeling, myocardial scar formation, extent of coronary artery disease, and residual ischemia may differ both quantitatively and qualitatively in patients with acute infarction compared to patients with chronic HF. Additionally, the extent of activation of cytokines, fibrinolytic balance, and activity of clotting factors may differ. Eplerenone was chosen for this study because of its demonstrated efficacy in an experimental model of AMI [6]. In clinical trials, eplerenone demonstrated efficacy similar to spironolactone in blocking aldosterone receptors, lowering blood pressure, and moderating hormonal and neurohormonal markers of HF [7, 8]. However, eplerenone has significantly less affinity for androgen and progesterone receptors and should therefore be associated with a lower incidence of gynecomastia, breast pain and impotency in males, and diminished libido and menstrual irregularities in females [9–11]. While older patients suffering from refractory HF may tolerate these androgenic and progestational side effects, they may preclude widespread use of a nonspecific aldosterone antagonist in younger patients or in patients with less severe cardiac compromise. Since eplerenone is at least 100 times more specific in its affinity for aldosterone receptors than is spironolactone, if the hypothesis being tested in the EPHESUS trial proves correct, eplerenone has the potential to be used in a broad population to prevent progressive left ventricular remodeling, ventricular fibrosis, malignant arrhythmias, non-fatal AMI, and sudden cardiac death. We hypothesize that selective aldosterone receptor blockade with eplerenone will have a beneficial effect on survival and morbidity in patients with AMI complicated by HF due to systolic left ventricular dysfunction. This paper describes the background, design, and organization of a trial to test this hypothesis—the EPHESUS trial (Eplerenone Post-AMI Heart Failure