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ST-segment elevation (STE) in the lead aVR indicates global ischemia of the myocardium and is often associated with obstructive coronary artery disease (CAD). We report a serial of cases presenting with STE in aVR and diffuse ST depressions in more than six other leads as a common feature, but of different etiologies, i.e., severe anemia due to gastrointestinal bleeding; drug over-dose-induced vasospasm and tachycardia, and severe CAD involving distal left main and ostial right coronary arteries, which required specific management approaches. We categorize the possible causes of STE in aVR with or without diffuse ST depression ECG according to whether anticoagulation/antithrombotic agents are indicated, contra-indicated, and propose a systematic approach in evaluating and managing these patients.