Current guidelines recommend against revascularization of the noninfarct artery during the index percutaneous coronary intervention (PCI) in hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI). This was based largely on observational studies with few data coming from randomized controlled trials (RCTs). Recently, several small-to-moderate sized RCTs have provided data, suggesting that a multivessel revascularization approach may be appropriate. We performed a meta-analysis of RCTs comparing multivessel percutaneous coronary intervention (MV PCI) versus culprit vessel–only revascularization (COR) during primary PCI in patients with STEMI and multivessel coronary disease (MVCD). We searched Medline, PubMed, and Scopus databases for RCTs comparing MV PCI versus COR in patients with STEMI and MVCD. The incidence of all-cause death, cardiac death, recurrent myocardial infarction, and revascularization during follow-up were extracted. Four RCTs fit our primary selection criteria. Among these, 566 patients underwent MV PCI (either at the time of the primary PCI or as a staged procedure) and 478 patients underwent COR. During long-term follow-up (range 1 to 2.5 years), combined data indicated a significant reduction in all-cause mortality (relative risk [RR] 0.57, 95% confidence interval [CI] 0.36 to 0.92, p = 0.02) and in cardiac death (RR 0.38, 95% CI 0.20 to 0.73, p = 0.004) with MV PCI. In addition, there was a significantly lower risk of recurrent myocardial infarction (RR 0.41, 95% CI 0.23 to 0.75; p = 0.004) and future revascularization (RR 0.37, 95% CI 0.27 to 0.52; p <0.00001). In conclusion, from the RCT data, MV PCI appears to improve outcomes in patients with STEMI and MVCD.