Objectives This study was designed to compare the outcomes of paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) in a contemporaneous cohort of real-world patients. Background A number of randomized comparisons of PES and SES have shown unequivocal advantages for SES in anglographic end points such as late loss. However, the data on clinical outcomes are less consistent. Methods All consecutive patients successfully treated with only SES or PES in de novo native vessel lesions between March 2003 and March 2005 were analyzed. Our end points were major adverse cardiac events (MACE), a composite of death, myocardial infarction (MI), target vessel revascularization (TVR), and target lesion revascularization (TLR). We also analyzed late loss and angiographic restenosis. Results There were 609 patients (1,064 lesions) treated with PES and 674 patients (1,205 lesions) treated with SES. Diabetes mellitus was present in 26.8% of patients and multivessel disease in 75% of patients. Bifurcations made up 16.3% of lesions, chronic occlusions 9.5%, left main 4.8%, and American Heart Association/American College of Cardiology type B2/C 75.4%. Despite a higher late loss in the PES group (p = 0.0001), there were no differences in anglographic restenosis (PES 18% vs. SES 17.8%, p = 0.95), TLR (PES 11.9% vs. SES 11%, p 0.47), or MACE (PES 21.3% vs. SES 21.1%, p = 0.95). The relative risk of MACE for the PES group was 1.02 (95% confidence interval [Cl] 0.78 to 1.33). Multivariable analysis confirmed the lack of association of stent type with MACE (odds ratio 1.03 [95% Cl 0.77 to 1.38], p = 0.83) and TLR (odds ratio 1.08 [95% Cl 0.81 to 1.44], p = 0.61). Conclusions In this complex cohort, both stent platforms demonstrated similar clinical outcomes despite different late loss.