Objectives: To compare clinical outcomes among patients with acute coronary syndrome treated with zotarolimus-eluting and sirolimus-eluting stents in the SORT OUT III trial. Background: Currently, only limited data allow direct comparison of clinical outcomes among patients with acute coronary syndrome treated with a second-generation drug-eluting stent (DES) eluting zotarolimus vs. a first-generation DES eluting sirolimus. Methods: Patients with acute coronary syndrome (n=1052) were randomized to treatment with zotarolimus-eluting (n=506) or sirolimus-eluting (n=546) stents and followed for 18months. The primary composite endpoint, major adverse cardiac events (MACE), was defined as a composite of cardiac death, myocardial infarction or target vessel revascularization. Results: Zotarolimus-eluting stent treatment compared to sirolimus-eluting stent treatment was associated with increased rates of MACE (8·7% vs. 5·0%; hazard ratio (HR), 1·78; 95% confidence interval (CI), 1·10-2·88; P=0·02) and TVR (6·8% vs. 3·9%; HR, 1·77; 95% CI, 1·03-3·04; P=0·04), while all-cause death, cardiac death, myocardial infarction and definite stent thrombosis did not differ significantly. In the same trial, stable angina pectoris patients (n=1206) were randomized to zotarolimus-eluting (n=614) and sirolimus-eluting (n=592) stents with similar results. Conclusions: With and without acute coronary syndromes, patients treated with the sirolimus-eluting stent had better clinical outcomes than those treated with the zotarolimus-eluting stent.