The effect of insulin therapy on adverse cardiovascular outcomes in diabetic patients has been debated and a reduced benefit in clinical restenosis outcomes after sirolimus stenting has been reported among diabetic patients requiring insulin therapy. We analyzed 297 diabetic patients receiving sirolimus-eluting stents, including 115 (39%) on insulin therapy, and compared outcomes with 541 nondiabetic patients treated consecutively during the same interval. The rates of target lesion revascularization (9.5% vs 3.5%, p = 0.003) and cardiac death or myocardial infarction (MI, 7.1% vs 3.1%, p = 0.012) were significantly higher for diabetic patients. Insulin treatment was independently associated with increased risk for target lesion revascularization (odds ratio [OR] 2.48, 95% confidence interval [CI] 1.22 to 5.00) and cardiac death or MI (hazard ratio [HR] 2.85, 95% CI 1.41 to 5.77), whereas the adjusted risk for diabetic patients not treated with insulin was not significantly different from patients without diabetes for target lesion revascularization (OR 1.32, 95% CI 0.66 to 2.62) or cardiac death or MI (HR 1.04, 95% CI 0.50 to 2.17). In conclusion, diabetes mellitus is associated with increased risk for target lesion revascularization and cardiac death or MI after receiving sirolimus-eluting stenting, and is significantly exaggerated by the requirement for insulin therapy.