ST-segment elevation in lead aVR in patients with angina at rest can be related to transmural ischemia of the basal part of the interventricular septum, frequently due to left main or multivessel coronary disease. However, this electrocardiographic (ECG) sign may also occur in other clinical conditions manifesting by acute chest pain. We present a case of a 76-year-old Caucasian woman with transient ST-segment elevation in lead aVR associated with tako-tsubo cardiomyopathy. Our report seems to confirm the hypothesis about the role of reversible myocardial ischemia involving the basal part of the interventricular septum in the pathogenesis of tako-tsubo cardiomyopathy. In conclusion, ST-segment elevation in lead aVR in patients with a clinical presentation of acute coronary syndrome may be not related to coronary artery disease. Tako-tsubo cardiomyopathy should be considered among the causes of ST-segment elevation in lead aVR in patients with angina at rest. Further studies are needed to evaluate the occurrence and importance of this ECG sign in patients with tako-tsubo cardiomyopathy.