In acute ST-elevation myocardial infarction (STEMI), patients with multivessel disease (MVD) are considered to be a subgroup with an increased risk of mortality compared with patients with single-vessel disease (SVD). To evaluate the effect of MVD on 1-year mortality in patients with STEMI, we studied 1,417 consecutive patients with STEMI who were admitted between 1997 and 2002 and treated with primary percutaneous coronary intervention. Further, we hypothesized that the effect of MVD on mortality is due to the presence of a chronic total occlusion in a noninfarct-related artery. Patients with MVD and/or a chronic total occlusion had multiple differences in baseline and angiographic characteristics that were associated with worse outcome. Mortalities in patients with SVD, MVD, and a chronic total occlusion were 8%, 16%, and 35%, respectively. After correction for the baseline differences, MVD was an independent predictor of mortality (odds ratio 1.5, 95% confidence interval 1.1 to 2.1). However, when chronic total occlusion was included in the model, MVD was no longer an independent predictor for mortality, whereas chronic total occlusion was a strong and independent predictor for 1-year mortality in patients with STEMI treated with percutaneous coronary intervention (odds ratio 3.8, 95% confidence interval 2.5 to 5.8). In conclusion, patients with STEMI and MVD have a higher 1-year mortality rate compared with patients with SVD, which is mainly determined by the presence of a chronic total occlusion in a noninfarct-related artery. In the setting of primary percutaneous coronary intervention, the presence of a chronic total occlusion, and not the mere presence of MVD, is an independent predictor of mortality.