Using well-established ex vivo techniques with RBCs collected from STEMI patients at admission administered to an isolated rat heart model of ischemia–reperfusion, we demonstrate that RBCs from STEMI patients reduce infarct size and improve post-ischemic cardiac function via a mechanism involving purinergic P2Y13 receptor-mediated NO–sGC signaling. This evidence concerns the gene P2RY13 and ST Elevation Myocardial Infarction.