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Background: The optimal percutaneous interventional strategy for dealing with significant non-culprit lesions in patients with multivessel disease (MVD) with acute myocardial infarction (AMI) at presentation remains controversial., Methods: A total of 820 patients treated with primary angioplasty for AMI between 1998 and 2002 were classified in groups of patients with single vessel disease (SVD) or MVD (> or =70% stenosis of > or =2 coronary arteries). Patients with MVD were subdivided in 3 groups on the basis of the revascularization strategy: 1) patients undergoing percutaneous coronary intervention (PCI) of the infarct-related artery (IRA) only; 2) patients undergoing PCI of both the IRA and non-IRA(s) during the initial procedure; and 3) patients undergoing PCI of the IRA followed by staged, in-hospital PCI of the non-IRA(s). Procedural, 30-day, and 1-year outcomes are reported., Results: At 1 year, compared with patients with SVD, patients with MVD had a higher incidence of re-infarction (5.9% vs 1.6%, P =.003), revascularization (18% vs 9.6%, P <.001), mortality (12% vs 3.2%, P <.001), and major adverse cardiac events (MACEs; 31% vs 13%, P <.001). In patients with MVD, compared with PCI restricted to the IRA only, multivessel PCI was associated with higher rates of re-infarction (13.0% vs 2.8%, P <.001), revascularization (25% vs 15%, P =.007), and MACEs (40% vs 28%, P =.006). Multivessel PCI was an independent predictor of MACEs at 1 year (odds ratio = 1.67, P =.01)., Conclusions: These data suggest that in patients with MVD, PCI should be directed at the IRA only, with decisions about PCI of non-culprit lesions guided by objective evidence of residual ischemia at late follow-up. Further studies are needed to confirm these findings.