BACKGROUND: Complete revascularization has been shown to be superior to culprit-only treatment in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. However, it remains unclear whether complete revascularization should be guided by coronary physiology or conventional angiography. Angiography-derived physiology may allow functional assessment and procedural guidance using angiograms from primary percutaneous coronary intervention (PCI), potentially maximizing the benefits of a physiology-guided approach. We present the design of a dedicated study that will address this research gap. METHODS AND DESIGN: The Functional Coronary Angiography to Indicate and Guide Revascularization in STEMI Patients with Multivessel Disease (AIR-STEMI) trial is a prospective, randomized, international, multicenter, open-label study with blinded adjudicated evaluation of outcomes. After successful treatment of the culprit lesion, patients will be randomized to receive PCI of the non-culprit lesions guided by conventional angiography or by angiography-derived fractional flow reserve (FFR). The primary endpoint is the composite endpoint of all-cause death, any myocardial infarction (MI), any cerebrovascular accident, or any revascularization. It will be censored once the last enrolled patient reaches 1-year follow-up. The secondary endpoint will be the composite of cardiovascular death or MI and each single component of the primary endpoint. All endpoints will be tested also at 3 and 5 years. The sample size for the study is a minimum of 1800 patients. IMPLICATIONS: The AIR-STEMI trial will provide novel evidence on whether a specific complete revascularization strategy should be applied to patients with STEMI and multivessel disease to improve their clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05818475.