Arrhythmogenic right-ventricular dysplasia (ARVD), a cardiomyopathy inherited as an autosomal-dominant disease, is characterized by fibro-fatty infiltration of the right-ventricular myocardium. Four loci for ARVD have been mapped in the Italian population, and recently the first locus was mapped in inhabitants of North America. None of the genes have been identified. We have now identified another North American family with early onset of ARVD and high penetrance. All of the children with the disease haplotype had pathological or clinical evidence of the disease at age <10 years. The family spans five generations, having 10 living and 2 dead affected individuals, with ARVD segregating as an autosomal-dominant disorder. Genetic linkage analysis excluded known loci, and a novel locus was identified on chromosome 10p12-p14. A peak two-point LOD score of 3.92 was obtained with marker D10S1664, at a recombination fraction of 0. Additional genotyping and haplotype analysis identified a shared region of 10.6 cM between marker D10S547 and D10S1653. Thus, a novel gene responsible for ARVD resides on the short arm of chromosome 10. This disease is intriguing, since it initiates exclusively in the right ventricle and exhibits pathological features of apoptosis. Chromosomal localization of the ARVD gene is the first step in identification of the genetic defect and the unraveling of the molecular basis responsible for the pathogenesis of the disease.