Background - Although the effects of epicardial implantable cardioverter-defibrillator (ICD) leads on underlying cardiac tissue have been reported, the gross and microscopic changes associated with endocardial ICD leads are less well described. This study describes the gross and microscopic changes associated with endocardial ICD leads in humans. Methods and Results The hearts from 8 patients were examined. At the time of ICD implantation, the patients' mean age was 47±11 years, and the left ventricular ejection fraction was 0.24±0.10. Four patients had ischemic heart disease, and 4 had dilated cardiomyopathy. Five hearts were examined after transplantation; 3, after death. The electrode-myocardial interfaces were characterized by intense endocardial fibrosis and were remarkably Consistent. Each lead was encased by a ring of fibroelastic tissue, and there was fibrosis of the right ventricular myocardium adjacent to the leads. Fibrosis involved the tricuspid valve in 5 patients, and 1 had perforation of the valve by the lead. Microscopically, interstitial fibrosis was adjacent to each lead in the current path of ICD shocks. Acute cell injury was present only in the hearts that had received recent shocks. Conclusions - The ICD electrode-myocardial interface is characterized by intense fibrosis. The fibrosis associated with endocardial ICD leads and the cumulative acute damage produced by defibrillation discharges may explain Changes in the defibrillation and pacing thresholds and the difficulty of lead extraction thai can be encountered with transvenous ICD systems.