An initial electrocardiogram (ECG) and serial troponin measurements are both independently and incrementally predictive of acute coronary syndrome in patients presenting with undifferentiated chest pain in the Emergency Department (ED). However, it is unclear if serial (ECGs) add significant to the contemporary diagnostic evaluation of this patient group. The ASAP CATH study was a single center, prospective study that enrolled patients presenting to an ED with undifferentiated chest pain. In addition to standard clinical evaluation, serial ECGs were performed at 90-minute intervals to evaluate whether serial changes suggestive of ischemia developed (Q waves, ST elevation or depression, or T-wave inversion). Total 365 subjects were enrolled from March 2014 to May 2015. Serial ECG changes developed in 6.6% (n = 24 of 365), the most common being the development of T-wave inversion (66.7%, n = 16 of 24). The sensitivity and positive predictive value of serial ECG changes were poor (<30%), with a less areas under the curve (0.55) compared with serial troponins alone (0.83). The addition of serial ECG changes to Thrombolysis In Myocardial Infarction risk scoring showed a decrease in the net reclassification index for major adverse cardiovascular events (-0.04, p <0.1) and was not significant for the prediction of major adverse cardiovascular events and/or acute coronary syndrome in 30 days (-0.003, p = 0.94). In conclusion, routine serial ECG evaluation for patients presenting with undifferentiated chest pain in the ED may not significantly improved diagnostic prognosis beyond current standard evaluation modalities.