IN the congenital long-QT syndrome, prolongation of the cardiac action potential occurs by an unknown mechanism(1,2) and predisposes individuals to syncope and sudden death as a result of ventricular arrhythmias(3), Genetic heterogeneity has been demonstrated for autosomal dominant long-QT syndrome by the identification of multiple distinct loci(4,5), associated mutations in two candidate genes have recently been reported(6,7). One form of hereditary long QT (LQT3) has been linked to a mutation(7) in the gene encoding the human heart voltage-gated sodium-channel alpha-subunit (SCN5A on chromosome 3p21)(8). Here we characterize this mutation using heterologous expression of recombinant human heart sodium channels, Mutant channels show a sustained inward current during membrane depolarization, Single-channel recordings indicate that mutant channels fluctuate between normal and non-inactivating gating modes. Persistent inward sodium current explains prolongation of cardiac action potentials, and provides a molecular mechanism for this form of congenital long-QT syndrome.