Background: Best revascularization strategy in patients with acute coronary syndromes (ACS) and unprotected left main (ULM) coronary disease is still debate reflecting lack of convincing data. Objectives: To assess clinical feasibility and efficacy of ULM percutaneous coronary intervention (PCI) in patients with ACS and describe the practice of a center without on-site surgical back-up over a 7-year period. Methods: Data on high-risk patients with ACSs undergoing percutaneous ULM treatment were prospectively collected in an independent registry. Primary end-points of this study were immediate and long-term outcomes expressed as target lesion failure (TLF, composite of cardiac death, myocardial infarction (MI), and target lesion revascularization). Results: Between January 2003 and January 2010, 200 consecutive patients were included in this study. Angiographic success was obtained in 95% of patients but procedural success was 87% primarily affected by an 11% of in-hospital cardiac mortality. At median follow-up of 26 months (IQ 10–47), the overall TLF rate was 28.5%, with 16.0% of cardiac death, 7.0% of MI, and 10.5% of clinically driven target lesion revascularization rates. Cumulative definite/probable stent thrombosis was 3.5%. Elevated EuroSCORE value and pre-procedural hemodynamic instability were the strongest predictors of TLF. Temporal trend analysis showed progressive but not significant improvement for both immediate (P = 0.110) and long-term (P = 0.073) outcomes over the study period. Conclusions: This single-center study based on current clinical practice in patient with ULM disease and ACS confirmed PCI as feasible revascularization strategy in absence of on-site cardio-thoracic support. Nevertheless, the outcome of these high-risk patients is still hampered by a sensible in-hospital mortality rate. © 2011 Wiley Periodicals, Inc.