Objectives: To compare long-term clinical outcomes between intravascular ultrasound (IVUS)-guided and angiography-guided percutaneous coronary intervention (PCI) in a large “real world” registry. Background: The impact of IVUS-guided PCI on clinical outcomes remains unclear. Methods: Between January 1998 and February 2006, 8,371 patients who underwent IVUS- (n = 4,627) or angiography- (n = 3,744) guided PCI were consecutively enrolled. Three-year clinical outcomes were compared after adjustment for inverse-probability-of-treatment weighting (IPTW) in the overall population and in separate populations according to stent type. Results: A crude analysis of the overall population showed that the 3-year mortality rate was significantly lower in the IVUS-guided group than in the angiography-guided group (96.4% ± 0.3% vs. 93.6% ± 0.4%, log-rank P < 0.001). When adjusted by IPTW, patients undergoing IVUS-guided PCI remained at lower risk of mortality (hazard ratio [HR] 0.627; 95% CI 0.50–0.79, P < 0.001). Similarly, in the drug-eluting stent (DES) population, the 3-year risk of mortality was significantly lower in patients undergoing IVUS-guided PCI (HR 0.46; 95% CI 0.33–0.66, P < 0.001). In contrast, IVUS-guided PCI did not reduce the risk of mortality in the bare metal stent population (HR 0.82; 95% CI 0.60–1.10, P = 0.185). However, the risks of myocardial infarction (HR 0.95; 95% CI 0.63–1.44, P = 0.810), target vessel revascularization (HR 1.00; 95% CI 0.86–1.15, P = 0.944), and stent thrombosis (HR 0.82; 95% CI 0.53–1.07, P = 0.109) were not associated with IVUS guidance. Conclusions: IVUS-guided PCI may reduce long-term mortality when compared with conventional angiography-guided PCI. This may encourage the routine use of IVUS for PCI in patients undergoing DES implantation. © 2012 Wiley Periodicals, Inc.