Background: The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarct (MI) size in the pre-clinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction (MVO) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Methods: This was a Phase 2, multi-center, randomized, double-blind, placebo controlled clinical trial conducted between November 2017 to November 2021 in six cardiac centers in Singapore (NCT03102723). Patients were randomized to receive either cangrelor or placeboinitiated prior to the PPCI procedure on top of oral ticagrelor. The key exclusion criteria included: presenting <6 hours of symptom onset, prior MI and stroke or transient ischemic attack; on concomitant oral anticoagulants; and a contraindication for cardiovascular magnetic resonance (CMR). The primary efficacy endpoint was acute MI size by CMR within the first week expressed as percentage of the left ventricle mass ( %LVmass). MVO was identified as areas of dark core of hypoenhancement within areas of late gadolinium enhancement. The primary safety endpoint was Bleeding Academic Research Consortium (BARC)-defined major bleeding in the first 48 hours. Continuous variables were compared by Mann-Whitney U test [reported as median (1st quartile- 3rd quartile)] and categorical variables were compared by Fisher's exact test. A 2-sided P<0.05 was considered statistically significant. Results: Of 209 recruited patients, 164 patients (78% ) completed the acute CMR scan. There were no significant differences in acute MI size [placebo: 14.9 (7.3 - 22.6) %LVmass versus cangrelor: 16.3 (9.9 - 24.4)%LVmass, P=0.40] or the incidence [placebo: 48% versus cangrelor: 47%, P=0.99] and extent of MVO [placebo:1.63 (0.60 - 4.65)%LVmass versus cangrelor: 1.18 (0.53 - 3.37)%LVmass, P=0.46] between placebo and cangrelor despite a two-fold decrease in platelet reactivity with cangrelor. There were no BARC-defined major bleeding events in either group in the first 48 hours. Conclusions: Cangrelor administered at time of PPCI did not reduce acute MI size or prevent MVO in STEMI patients given oral ticagrelor despite a significant reduction of platelet reactivity during the PCI procedure.