Background The long-term relative benefit of culprit-only percutaneous coronary intervention (PCI) and staged PCI in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease remains disputable. This study aimed to compare the long-term outcomes of culprit-only PCI and in-hospital staged complete revascularization in real-world patients with STEMI and multivessel coronary artery disease. Patients and methods A total of 452 patients were treated with in-hospital staged complete revascularization (n=133) or culprit-only PCI (n=319) between May 2012 and December 2015 in our center. The primary end point was major adverse cardiac and cerebrovascular event (MACCE), defined as a composite of all-cause death, nonfatal myocardial infarction, stroke, and unplanned revascularization. Results The median follow-up period was 3.2 years. Overall, treatment with in-hospital staged complete revascularization can reduce the incidence of the primary end point of MACCE in both the overall population [hazard ratio (HR): 0.48; 95% confidence interval (CI): 0.29-0.82] and the propensity-matched cohorts (HR: 0.51; 95% CI: 0.27-0.97). After correction of the possible confounders, staged PCI remained associated with decreased risk of MACCE (HR: 0.56; 95% CI: 0.33-0.96). Besides, the strategy of staged PCI tended to be associated with lower risk of a composite of cardiac death, myocardial infarction, and stroke than culprit-only PCI in multivariable-adjusted analysis (HR: 0.30; 95% CI: 0.09-1.01). Conclusion In patients with STEMI and multivessel disease undergoing primary PCI, an approach of in-hospital staged complete revascularization was associated with a better 3-year composite outcome compared with culprit-only PCI. Copyright (c) 2019 Wolters Kluwer Health, Inc. All rights reserved.