Approximately half of patients with ST-segment elevation myocardial infarction (STEMI) present with non-infarct related multivessel coronary artery disease (CAD) during primary percutaneous coronary intervention (PCI). However, questions remain concerning whether patients with STEMI and multivessel CAD should routinely undergo complete revascularization. Our objective was to compare the risks of major cardiovascular outcomes and procedural complications in patients with STEMI and multivessel CAD randomized to complete revascularization versus culprit-only PCI. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing complete revascularization to culprit-only PCI. RCTs were identified via a systematic search of MEDLINE, Embase, and Cochrane CENTRAL. Count data were pooled using DerSimonian and Laird random-effects models with inverse variance weighting to obtain relative risks (RRs) and 95% confidence intervals (CIs). A total of 9 RCTs (n=6,751) were included, with mean/median follow-up times ranging from six to 36 months. Compared with culprit-only PCI, complete revascularization was associated with a substantial reduction in major adverse cardiovascular events (13.1% vs. 22.1%; RR: 0.54; 95% CI: 0.43-0.66), repeat myocardial infarction (4.9% vs. 6.8%; RR: 0.64; 95% CI: 0.48-0.84), and repeat revascularization (3.7% vs. 12.3%; RR: 0.33; 95% CI: 0.25-0.44). Complete revascularization may have beneficial effects on all-cause and cardiovascular mortality, but 95% CIs were wide. Findings for stroke, major bleeding, and contrast-induced acute kidney injury were inconclusive. In conclusion, complete coronary artery revascularization appears to confer benefit over culprit-only PCI in patients with STEMI and multivessel CAD, and should be considered a first-line strategy in these patients.