Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a specific heart muscle disease of unknown etiology characterized by fatty and fibrofatty replacement of the right ventricular myocardium. It often manifests life-threatened ventricular arrhythmias. Previous studies have hypothesized that myocyte apoptosis contributes to the myocyte cell loss and fatty change in ARVC and may be induced by recurrent ventricular tachycardia (VT). We examined whether these progressive pathological changes result from apoptotic cell death in both autopsied and biopsied right ventricular myocardium from 35 patients with ARVC by using in situ terminal deoxynucleotidyl transferase assay (TUNEL) and agarose gel electrophoresis. We also studied the biopsied myocardium from 30 patients with idiopathic sustained VT whose origin was the outflow tract of the right ventricle. TUNEL-positive cells indicating DNA fragments were observed in some cardiomyocytes and fibroblasts in ARVC, but the numbers of TUNEL-positive myocytes were very low in idiopathic VT. DNA laddering was confirmed in two autopsied cases in ARVC, but not in a non-cardiac case who died. These results suggest that at least some cardiomyocytes and fibroblasts are subjected to apoptosis in ARVC, leading to the loss of myocardium with characteristic pathological changes and subsequently progressive cardiomyopathy. Furthermore, the apoptotic process may not result from myocardial ischemia due to repetitive VT.