BACKGROUND: Myocardial salvage is often suboptimal after percutaneous coronary intervention in ST-segment elevation myocardial infarction. Posthoc subgroup analysis from a previous trial (AMIHOT I) suggested that intracoronary delivery of supersaturated oxygen (SSO(2)) may reduce infarct size in patients with large ST-segment elevation myocardial infarction treated early. METHODS AND RESULTS: A prospective, multicenter trial was performed in which 301 patients with anterior ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention within 6 hours of symptom onset were randomized to a 90-minute intracoronary SSO(2) infusion in the left anterior descending artery infarct territory (n=222) or control (n=79). The primary efficacy measure was infarct size in the intention-to-treat population (powered for superiority), and the primary safety measure was composite major adverse cardiovascular events at 30 days in the intention-to-treat and per-protocol populations (powered for noninferiority), with Bayesian hierarchical modeling used to allow partial pooling of evidence from AMIHOT I. Among 281 randomized patients with tc-99m-sestamibi single-photon emission computed tomography data in AMIHOT II, median (interquartile range) infarct size was 26.5% (8.5%, 44%) with control compared with 20% (6%, 37%) after SSO(2). The pooled adjusted infarct size was 25% (7%, 42%) with control compared with 18.5% (3.5%, 34.5%) after SSO(2) (P(Wilcoxon)=0.02; Bayesian posterior probability of superiority, 96.9%). The Bayesian pooled 30-day mean (+/-SE) rates of major adverse cardiovascular events were 5.0+/-1.4% for control and 5.9+/-1.4% for SSO(2) by intention-to-treat, and 5.1+/-1.5% for control and 4.7+/-1.5% for SSO(2) by per-protocol analysis (posterior probability of noninferiority, 99.5% and 99.9%, respectively). CONCLUSIONS: Among patients with anterior ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention within 6 hours of symptom onset, infusion of SSO(2) into the left anterior descending artery infarct territory results in a significant reduction in infarct size with noninferior rates of major adverse cardiovascular events at 30 days. Clinical Trial Registration- clinicaltrials.gov Identifier: NCT00175058.