American College of Cardiology/American Heart Association guidelines for management of patients with ST-segment elevation myocardial infarction (STEMI) recommend culprit artery-only revascularization (CULPRIT) based on safety concerns during noninfarct-related artery intervention. However, the data to support this safety concern are scant. Searches were performed in PubMed/EMBASE/CENTRAL for studies evaluating multivessel revascularization versus CULPRIT in patients with STEMI and multivessel disease (MVD). A multivessel revascularization strategy had to be performed at the time of CULPRIT or during the same hospitalization. Early (≤30-day) and long-term outcomes were evaluated. Among 19 studies (23 arms) that evaluated 61,764 subjects with STEMI and MVD, multivessel revascularization was performed in a minority of patients (16%). For early outcomes, there was no significant difference for outcomes of mortality, MI, stroke, and target vessel revascularization, with a 44% decrease in risk of repeat percutaneous coronary intervention and major adverse cardiovascular events (odds ratio 0.68, 95% confidence interval 0.57 to 0.81) with multivessel revascularization compared to CULPRIT. Similarly, for long-term outcomes (follow-up 2.0 ± 1.1 years), there was no difference for outcomes of MI, target vessel revascularization, and stent thrombosis, with 33%, 43%, and 53% decreases in risk of mortality, repeat percutaneous coronary intervention, coronary artery bypass grafting, respectively, and major adverse cardiovascular events (odds ratio 0.60, 95% confidence interval 0.50 to 0.72) with multivessel revascularization compared to CULPRIT. In conclusion, in patients with STEMI and MVD, multivessel revascularization appears to be safe compared to culprit artery-only revascularization. These findings support the need for a large-scale randomized trial to evaluate revascularization strategies in patients with STEMI and MVD.