Clinical outcomes after multivessel versus single-vessel percutaneous coronary intervention (PCI) in the era of stents, glycoprotein IIb/IIIa inhibitors, and clopidogrel pretreatment have not been well studied. Thus, we compared outcomes from the Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial (TARGET) for patients who underwent multivessel versus single-vessel PCI and separately considered the effect of acute coronary syndromes on the results. Composite clinical outcomes (death, myocardial infarction, and target vessel revascularization) were evaluated at 30 days and 6 months and mortality at 1 year. Safety analysis included in-patient major and minor bleeding. Despite similar baseline characteristics, patients who underwent multivessel PCI (n = 775) had significantly higher 30-day and 6-month composite event rates than did those who were treated in a single coronary artery territory (n = 3,969). This association remained significant at 30 days (hazard ratio 1.57, 95% confidence interval 1.06 to 2.33, p = 0.025) after using propensity matching to minimize confounding factors. The higher event rate was primarily due to an increase in periprocedural myocardial infarction. However, there were no significant differences in propensity-matched ischemic outcomes at 6 months and 1 year or in bleeding. In addition, in a propensity-matched analysis that included 810 patients with acute coronary syndrome, multivessel stenting resulted in numerically more ischemic events than did single-vessel stenting, although this did not reach statistical significance (hazard ratio 1.32, 95% confidence interval 0.85 to 2.05, p = 0.221). In conclusion, multivessel PCI was more often associated with periprocedural myocardial infarction than single-vessel intervention, although this did not translate into higher 1-year mortality. A randomized trial comparing multivessel PCI with staged or surgical revascularization is warranted.