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The conventional strategy for primary angioplasty during acute myocardial infarction is angioplasty of the infarct-related vessel, even in patients with multi-vessel disease. Patients, however, often have significant lesions in multiple coronary arteries and a strategy for multi-vessel angioplasty during acute myocardial infarction has not been explored. The purpose of this study was to examine whether multi-vessel angioplasty is as safe as infarct-related vessel angioplasty in patients with multi-vessel coronary artery disease during acute myocardial infarction.Using the 2000–2001 New York State Angioplasty Registry database, we compared the in-hospital clinical outcomes of patients with multi-vessel disease (>70% stenosis in at least two major coronary arteries), who underwent either multi-vessel angioplasty (n=632) or infarct-related vessel angioplasty (n=1350) within 24 h of acute myocardial infarction. Patients with previous myocardial infarction, angioplasty, bypass surgery, or cardiogenic shock were excluded.Patients in the multi-vessel angioplasty group were less likely to be female, to have peripheral vascular disease or diabetes. They had more complex lesions and were more likely to receive stents. In-hospital mortality was three-fold lower (0.8 versus 2.3%, P=0.018) in the multi-vessel angioplasty group. No differences were observed in other ischemic complications, renal failure, or length of stay. After multivariate analysis, multi-vessel angioplasty remained a significant predictor of lower in-hospital death (odds ratio=0.27, 95% confidence interval=0.08–0.90, P=0.03).Despite the added complexity of multi-vessel angioplasty, patients in this group had significantly lower in-hospital mortality. Therefore, a strategy of multi-vessel angioplasty during acute myocardial infarction may be safe compared with infarct-related angioplasty in selected patients.