Background-Hospital prognosis of moderate to severe pericardial effusion (MPE; Ն10 mm) in ST-elevation myocardial infarction is largely unknown. Methods and Results-Data from 446 ST-elevation myocardial infarction patients, 228 with MPE-88 with cardiac tamponade (CT) and electromechanical dissociation (EMD), 44 with CT without EMD (w/oEMD), and 96 without initial CT-and 218 with small PE (5 to 9 mm), were compared. Patients with MPE without initial CT were also compared with 96 patients without PE. CT patients showed larger PE (PϽ0.001) than those without initial CT; 85% of those with CTϩEMD and 86% with CTw/oEMD were treated with pericardiocentesis and 10% and 21% were treated with a surgical repair, respectively. Among MPE patients, 30-day mortality was 43% and was higher in those with CTϩEMD (operated, 89%; and nonoperated, 85%) than in those with CTw/oEMD (22% and 11%, respectively; PϽ0.001) and those without initial CT (17%; PϽ0.001). It was also higher than in patients with small PE (10%; PϽ0.001) or those without PE (6%; Pϭ0.001). Death was attributable to cardiac rupture in 83% of patients with CTϩEMD, 7% with CTw/oEMD, and 8% with MPE without initial CT and occurred late (Ն7 days) in 14%, 67%, and 100%, respectively. Conclusions-MPE carries an increased mortality that is highest in patients with CTϩEMD. In those with CTw/oEMD, however, mortality is considerably low after pericardiocentesis, and subsequent management may be individualized because a conservative approach is often successful. Importantly, MPE patients without initial CT are not free from late rupture and deserve further investigation.