Background: Prior studies on the use of multivessel percutaneous coronary intervention (MV PCI) for patients with ST-segment–elevation myocardial infarction (STEMI) and multivessel coronary artery disease have yielded heterogeneous results. The recent COMPLETE trial (Complete Versus Culprit-Only Revascularization Strategies to Treat Multivessel Disease After Early PCI for STEMI) demonstrated that MV PCI was superior to culprit-only PCI among patients with STEMI. It is unclear how these trial results apply to clinical decisions encountered in routine practice. Methods: We studied STEMI admissions among patients >65 years with multivessel disease and Centers for Medicare and Medicaid Services–linked data in the National Cardiovascular Data Registry CathPCI Registry from July 1, 2009 to December 31, 2017. MV PCI was defined as PCI to a nonculprit lesion ≤45 days of the index procedure. The primary outcome was the composite of death, myocardial infarction, and revascularization from 45 days through 1 year. To account for unmeasured confounders, an instrumental variable analysis was used to compare treatment strategies. The instrument was institutional rates of MV PCI. A falsification end point of postdischarge major bleeding was utilized to assess for residual confounding. Results: Of 56 332 admissions from 1102 institutions, 37.7% received MV PCI ≤45 days of index STEMI PCI. Of those undergoing MV PCI, 74.8% received complete revascularization. In unadjusted analysis, MV PCI was associated with a lower cumulative incidence of the composite outcome between 45 days and 1 year (13.9% versus 18.2% for non-MV PCI, P <0.01). In the instrumental variable analysis, there was no association between MV PCI and the composite outcome (adjusted risk difference, −0.97% [95% CI, −3.52% to 1.59%]; P =0.46). An association between MV PCI and the falsification end point of major bleeding was not observed (adjusted risk difference, −2.54% [95% CI, −5.30% to 0.22%]; P =0.07). Conclusions: In this large, nationwide analysis, we did not find benefit of MV PCI by 1 year among older STEMI patients. The clinical benefit of MV PCI may not extend equally outside of trials to include all patients, including those with more extreme ages and more complex decision-making.