BACKGROUND: Reports of stent thrombosis and death in patients who have received drug-eluting stents (DES) have provoked debate regarding their long-term safety. We investigated the specific causes of death in patients receiving DES at an academic tertiary-care center. METHODS: A retrospective analysis of 1,023 consecutive patients who underwent percutaneous coronary intervention (PCI) with DES from 2003 to 2006 at UCLA Medical Center was performed. Dates and cause of death were obtained by reviewing the patient's medical record, contacting the patient's doctor, or accessing the Social Security Death Index and obtaining copies of death certificates at the Los Angeles County Registrar-Recorder/County Clerk office. If the cause of death could not be determined, it was reported "unknown." RESULTS: At a mean follow up of 2.9 +/- 1.3 years, 96 patients who underwent PCI with DES died during the analysis (9.4% mortality). The mean duration between index PCI and death was 331 +/- 324 days. The cause of death was unknown in 9 patients, thus the analysis was based upon 87 patients. There were similar number of cardiac (n = 44) and non-cardiac deaths (n = 43). The risk of PCI-related death was 1.3% (13/1023), which included 11 patients (1.1%) who died from stent thrombosis. Fourteen patients (1.4%) who presented with myocardial infarction (MI) and underwent PCI died, and 14 patients (1.4%) died from heart failure. Non-cardiac deaths included cancer, infection, respiratory failure and a cerebrovascular event. Age, chronic renal insufficiency, presentation with MI, chronic obstructive pulmonary disease, history of cerebrovascular event, orthotopic heart transplantation and left ventricular ejection fraction were significantly associated with increased mortality. CONCLUSIONS: Cardiac and non-cardiac causes of death contributed similarly to mortality in patients who underwent PCI with DES at a large tertiary care center that manages high-risk patients. Overall PCI-related death and stent thrombosis causing death were low. The majority of deaths occurred in patients after hospital discharge. The majority of patients who died in the hospital presented with acute MI and were in critical condition on presentation.