Among patients with acute myocardial infarction (MI) who have multivessel disease, it is unclear if multivessel percutaneous coronary intervention (PCI) improves clinical and quality-of-life outcomes compared with culprit-only intervention. We sought to compare clinical and quality-of-life outcomes between multivessel and culprit-only PCI. Among 6061 patients with acute MI who have multivessel disease in the TRANSLATE-ACS (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study, we used inverse probability-weighted propensity adjustment to study the associations between multivessel and culprit-only intervention during the index PCI and major adverse cardiovascular events, unplanned all-cause readmission, and angina frequency at 6 weeks and 1 year. Multivessel PCI was performed in 1208 (20%) of patients with MI who had multivessel disease. Relative to the culprit-only intervention, patients receiving multivessel PCI were similarly aged and more likely to be seen with non-ST-segment elevation MI or cardiogenic shock. At 6 weeks, the initial multivessel PCI strategy was associated with lower major adverse cardiovascular events and unplanned readmission risks, whereas angina frequency was not significantly different between multivessel and culprit-only PCI. At 1 year, major adverse cardiovascular event risk was persistently lower in the multivessel PCI group (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72-0.99), whereas long-term readmission risk (adjusted hazard ratio, 0.94; 95% confidence interval, 0.84-1.04) and angina frequency were similar between groups (adjusted odds ratio, 1.01; 95% confidence interval, 0.82-1.24). Similar associations were seen when patients with ST-segment elevation MI and non-ST-segment elevation MI were examined separately. Among patients with acute MI who have multivessel disease, multivessel PCI was associated with lower risk of all-cause readmission at 6 weeks and lower risk of major adverse cardiovascular events at 6 weeks and 1 year. However, similar short- and long-term angina frequencies were noted.