We examined the hypothesis that myocardial contrast echocardiography (MCE) is superior to conventional electrocardiographic, echocardiographic, and troponin I criteria for the diagnosis of acute coronary syndrome. We prospectively enrolled 114 consecutive patients (60+/-10 years of age, 73 men) who presented to the emergency room with chest pain on exertion and at rest. Exclusion criteria included an age<40 years, presence of Q wave or ST-segment elevation, and a poor echocardiographic window. Echocardiography and MCE were performed to assess regional wall motion abnormalities (RWMAs) and myocardial perfusion defects by using continuous infusion of perfluorocarbon-exposed sonicated dextrose albumin. Acute coronary syndrome was confirmed in 87 patients. There were no deaths; 46 patients had acute myocardial infarction, and 41 patients required urgent revascularization. On multiple logistic regression analysis, myocardial perfusion defect (odd ratio 87, p<0.001) was the only independent variable for diagnosing acute coronary syndrome. Myocardial perfusion defect (odd ratio 21, p=0.001) and troponin I levels (odd ratio 3, p=0.009) were independent predictors for acute myocardial infarction. The sensitivity of myocardial perfusion defect for diagnosing acute coronary syndrome was 77%, which is significantly higher than the sensitivities of ST change, troponin I increase, and RWMA (28%, 34%, and 49%, respectively), with similar specificities of 85% to 96%. In conclusion, MCE is more sensitive than the currently used electrocardiographic and troponin I criteria, and evaluation of myocardial perfusion defect by MCE complements RWMA analysis by conventional echocardiography for accurate diagnosis of acute coronary syndrome.