Patients with myocardial infarction routinely receive a platelet P2Y12 receptor antagonist prior to percutaneous coronary intervention. In monkeys, rabbits, and rats P2Y12 antagonists act as potent postconditioning-mimetics. Unlike ischemic postconditioning, however, the P2Y12 antagonist cangrelor could not reduce infarct size in Krebs buffer-perfused hearts. We tested whether platelets were required for protection from cangrelor. Rats were treated with intraperitoneal placebo or anti-rat thrombocyte serum (ARTS), 0.5ml, which decreased platelet counts by at least 96%. After 24h the heart was exposed and left coronary artery occluded for 30min and reperfused for 2h. Risk zone and infarct size were measured. In placebo rats infarct size averaged 45.3±1.2% of risk zone, while an intravenous bolus of cangrelor, 60μg/kg, 10 min before reperfusion followed by infusion of 6μg/kg/min decreased infarction to 25.0±1.8% (p<0.001). ARTS alone had no effect on infarct size (50.5±3.7%). However, ARTS blocked cangrelor’s protective effect (48.4±3.4% infarction). Hence cangrelor’s cardioprotective effect depends on platelets. But how can cangrelor cause platelets to trigger postconditioning’s protective signaling? Activated platelets release sphingosine -1 phosphate (S1P), a known trigger for conditioning. Some of the S1P from platelets comes from a sphingomyelinase that is recruited during activation and catabolizes membrane sphingomyelin to sphingosine (sph) which is quickly phosphorylated by sph kinases. We blocked sph kinase with intravenous N-N-dimethylsphingosine (DMS), 0.33 mg/kg, administered 15 min after coronary occlusion. DMS alone had no effect on infarction (43.8±2.3%). But it abrogated cangrelor’s protective effect (42.8±2.0%). In the presence of cangrelor platelets can’t aggregate and plug vascular defects caused by ischemic injury. We propose that in cangrelor-treated post-ischemic hearts platelets enter the interstitial space early in reperfusion and release S1P when they contact collagen which postconditions the heart and protects against reperfusion injury. Thus blocking aggregation allows platelets to produce a pharmacological trigger of postconditioning that reduces infarction.