Abstract Background and Aims The optimal timing of complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease complicated by heart failure remains uncertain. Methods The OPTION-STEMI (Optimal Timing of Fractional Flow Reserve-Guided Complete Revascularization for Non-Infarct-Related Artery in ST-segment Elevation Myocardial Infarction with Multivessel Disease) trial compared immediate vs staged complete revascularization during the index admission in patients with STEMI and multivessel disease. In the OPTION-STEMI trial, immediate complete revascularization was not found to be non-inferior for the primary endpoint compared with staged complete revascularization. Pre-specified subgroup analysis was performed according to heart failure at admission, defined as Killip class II or III. The primary endpoint was a composite of death from any cause, non-fatal myocardial infarction, or any unplanned revascularization at 1 year. Results Among 994 randomized patients, 329 (33.1%) had heart failure at admission. These patients had a higher risk of primary endpoint than those without heart failure (18.2% vs 8.7%; adjusted HR 1.63; 95% CI 1.11–2.40; P = .013). At 1 year, immediate complete revascularization was associated with a higher incidence of the primary endpoint than staged complete revascularization in patients with heart failure (22.8% vs 13.3%; HR 1.79; 95% CI 1.05–3.04), but not in those without heart failure (8.0% vs 9.5%; HR 0.84; 95% CI .50–1.40). A significant interaction was observed between heart failure status and randomized strategy (P = .043). Conclusions In the OPTION-STEMI trial, among patients with STEMI and multi-vessel disease who were not in cardiogenic shock, immediate complete revascularization was not non-inferior compared with staged complete revascularization. However, subgroup analysis suggests that the worse outcomes with immediate complete revascularization may be limited to patients with heart failure at admission. Further studies are required to demonstrate the non-inferiority of immediate complete revascularization compared with staged complete revascularization in patients without heart failure.