Abstract Background Although the standard 12-lead electrocardiogram (ECG) is considered the gold standard to diagnose acute myocardial ischemia, nearly half of ECGs are nondiagnostic in patients who present with chest pain and have subsequent confirmation of infarction with positive serum biomarkers. Methods A prospective study was performed to investigate the frequency and intensity of diastolic third and fourth heart sounds (S3 and S4), as measured by computerized acoustic cardiography, with myocardial ischemia induced by balloon occlusion during percutaneous coronary intervention. Results In our 24 subjects, during percutaneous coronary intervention–induced ischemia, a new or increased intensity S3 or S4 developed in 67%. Ten (67%) of 15 patients without clinical ST criteria for ischemia also developed new or increased-intensity diastolic heart sounds. Conclusions The combined use of diastolic heart sounds, as a measurement of ventricular dysfunction, with the standard ECG may improve the noninvasive diagnosis of myocardial ischemia that is likely to develop into infarction.