Aim. Aim of the present study was to assess stent- and patient-related outcomes of the first- vs. second-generation drug-eluting stents (DES) in diabetics, according to the insulin requirement status. Methods. Data were obtained from a prospective, single-center registry of 816 consecutive patients with diabetes mellitus (23% insulin-requiring) who underwent percutaneous coronary intervention (PCI) between April 2003 and May 2012 with first- (N.=534) or second-generation DES (N.=282) at our Institution, with at least 12 months of follow-up. We assessed the occurrence of stent-related outcome, including cardiac death, target vessel-related myocardial infarction and target lesion revascularization, versus patient-related outcome, including any cause death, any myocardial infarction and any coronary revascularization. Results. Patients treated with second-generation DES were older and had more complex lesions than patients treated with first-generation DES. Both among patients treated with first-generation DES and those treated with second generation DES, patient-related events were almost double than stent-related events. No interactions were observed between the DES generation type and insulin requirement status. Conclusion. In this observational study, first- and second-generation DES were equally safe and efficacious in diabetic patients undergoing PCI, regardless of insulin requirements. The greater number of patient-related than stent-related events in patients with complex clinical and lesion characteristics emphasizes that the optimization of secondary prevention is at least as important as the selection of which new generation DES to implant in a specific lesion.