Background: Takotsubo syndrome mimics acute myocardial infarction (MI) at presentation. Objectives: To explore differences in ECG time-course that could further help distinguish the two conditions. Methods: Serial ECG's (day 0–4) of 27 acute takotsubo and 37 MI patients, all presenting with anterior ST-elevation, were analysed for detailed morphology and timing of de/re-polarisation. All underwent cardiac magnetic resonance. Results: The presenting ECG (day 0) showed significantly fewer total abnormal leads (p = .001), comparable number of ST-elevation leads but lesser total magnitude of ST-elevation (p = .003), smaller sum of positive T wave amplitude (p = .006) and lesser number of pathological Q waves (p = .005) in takotsubo vs the MI group. After day 0, takotsubo patients developed more widespread T wave inversion (p = .001, day 3) and/or deeper T waves compared to MI, (sum of the T-wave amplitude slope of change between days 0–3: −43.1 ± 9.6 vs − 16.6 ± 5.4 mm, p = .02). Although there was no difference in mean QTc between the groups on any day, between days 0–3 there was a progressive increase in QTc in takotsubo vs a decrease in MI (34.1 ± 12.2 vs −29.5 ± 9.3 ms, slope of change p < .001). There was significantly more myocardial oedema (native T1 mapping) in takotsubo vs MI (p = .02), which resulted in increased left ventricular mass index in takostubo (p = .04). Conclusions: The differences in presenting (day 0) ECG between takotsubo and MI are significant but subtle, reinforcing the importance of acute cardiac catheterisation for accurate diagnosis. During the next 3 days there is progressive increase in the depth and spread of T-waves and QTc duration in takotsubo vs MI - these may aid the diagnostic confidence in patients with bystander non-obstructive coronary disease.