The primary aim of the study is to investigate the temporal changes in plasma lipidome before and after reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) and their association with myocardial injury. We found that 56% of the identified lipid species were significantly altered (corrected p< 0.05) in the first 24 h following reperfusion in patients with STEMI. Three lipid species, namely, acylcarnitine 18:2, TG 51:0, and LPC 17:1 were associated with a change in troponin concentration (delta troponin) and in-hospital cardiovascular events. Of these, acylcarnitine 18:2, and LPC 17:1 and their respective whole class levels, were significantly higher (p < 0.05) in the STEMI population than the age/sex-matched control subjects. Overall, our analyses showed a large shift in plasma lipidome in patients that undergo myocardial reperfusion. The differences found for acylcarnitines and LPC species and their association with both cardiac markers and cardiac outcomes need further validation. Display omitted •Human plasma lipidome rapidly shifts during myocardial reperfusion injury•Novel plasma lipids are associated with cardiovascular events•Acylcarnitines and lysoPCs correlate with the extent of myocardial injury•Acute MI results in elevated plasma AC 18:2 and LPC 17:1 compared to controls Cardiovascular medicine; Lipidomics