Primary Percutaneous Intervention (PCI) is the treatment of choice for acute ST-elevation myocardial infarction (STEMI). Nearly half of STEMI patients have multivessel (MV) disease that has been associated with worse survival. However, current guidelines recommend to treat only the culprit artery (COR) during the acute procedure. Thus, the aim of the current study was to perform a meta-analysis of trials comparing MV PCI vs. COR for STEMI patients with MV disease. Medline/CENTRAL and Web were searched for comparative studies (both randomized and non randomized trials) about MV PCI vs. COR for STEMI patients reporting mortality, re-PCI and re-MI data. Primary endpoint was 30-day mortality. The meta-analysis included 10 studies (2 randomized and 8 registries; N = 31224). As compared with COR, MV PCI significantly reduced long term rate of re-PCI (OR [95% CI] = 0.47 [0.28-0.78], P = 0.003) without increasing 30-day mortality (OR [95% CI] = 1.30 [0.79-2.12], P = 0.31) and long term re-MI (OR [95% CI] = 0.94 [0.43-2.06], P = 0.88). This meta-analysis showed safety and efficacy of MV PCI approach as compared with COR, with a significant reduction in rate of revascularizations, but no advantages in death and re-MI.